Pancreatic Neuroendocrine Neoplasms

Written by Anna Caterina Milanetto and Claudio Pasquali

Definition

Pancreatic neuroendocrine neoplasms are a heterogeneous group of neoplasms originating from the islets of Langerhans or endocrine cells scattered in the epithelial layer of the pancreatic ducts. These pancreatic neuroendocrine neoplasms exhibit different molecular and clinical features, with variable degrees of aggressiveness. Despite the fact that most are slow growing indolent tumors, they are still potentially malignant and may even show frank metastatic spread at the time of diagnosis.

Epidemiology

Pancreatic neuroendocrine neoplasms are rare, with an annual incidence of 1.5/100,000 individuals. However, this incidence has been rising over the past two decades, largely due to improved diagnostic techniques ¹. Older autopsy studies reported a prevalence of 2.5-3%, consistent with the 4% prevalence observed in resected pancreata ². This discrepancy between incidence and prevalence (almost a thousandfold) is attributed to the abundance of tiny “non-functioning” microadenomas (less than 5 mm in size) that will never progress or become symptomatic.

Pancreatic neuroendocrine neoplasms account for approximately 7% of all pancreatic neoplasms in case series. The median age at diagnosis ranges from 50 to 60 years. Earlier onset is typically associated with genetic conditions, such as multiple endocrine neoplasia type 1 (MEN1) syndrome, which accounts for 10-15% of pancreatic neuroendocrine neoplasms.

WHO Classification and Molecular Profiles

The latest World Health Organization (WHO) classification from 2019 categorizes neuroendocrine neoplasms into two main groups with distinct molecular profiles: neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) ³.

NETs are further graded into three categories according to histologic differentiation, Ki-67 proliferative index and mitotic index. Pancreatic NETs are commonly associated with MEN1 gene inactivation (44%; not all in the context of MEN1 syndrome), DAXX/ATRX gene mutations (43%) and, less frequently, with alterations in the mTOR pathway (15%).
NECs are classified into small and large cell NECs. NECs lack DAXX/ATRX mutations, but display TP53 or RB1 mutations in over 90% of cases ⁴.

A pancreatic neuroendocrine neoplasm mixed with an exocrine pancreatic neoplasm is called a mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN).

Genetic Syndromes and Susceptibility

A minority of patients with pancreatic neuroendocrine neoplasms have autosomal dominantly inherited genetic syndromes caused by germline mutations. These include:

Multiple Endocrine Neoplasia Type 1 (MEN1; most common)
Multiple Endocrine Neoplasia Type 4 (MEN4)
Neurofibromatosis Type 1
Von Hippel-Lindau Syndrome
Tuberous Sclerosis Complex

To further understand genetic susceptibility in sporadic pancreatic neuroendocrine neoplasms, Obazee et al. ⁵ identified specific single nucleotide polymorphisms (SNPs)—rs9543325, rs10919791, and rs1561927—that may increase the risk of developing pancreatic neuroendocrine tumors (pNETs).

Clinical Classification and presentation

Pancreatic neuroendocrine neoplasms are classified as functioning or non-functioning , according to whether they secrete active hormones that cause symptoms.

Although non-functioning pancreatic neuroendocrine neoplasms can secrete calcitonin, chromogranin, ghrelin, neuron-specific enolase (NSE), or pancreatic polypeptide, they do not present with a hormone-related syndromes ⁶. However, symptoms can arise from primary tumor growth (obstructive jaundice, diabetes, exocrine pancreatic insufficiency with steatorrhea and late weight loss) or metastatic spread.
Functioning pancreatic neuroendocrine neoplasms present with a clinical syndrome consistent with the hormones they secrete. Due to the associated symptoms, these tumors are generally diagnosed earlier and detected at a smaller size than non-functioning pancreatic neuroendocrine neoplasms.
- Insulinomas (70% of functioning pancreatic neuroendocrine neoplasms) hypersecrete insulin, causing hypoglycemia, which manifests with adrenergic symptoms such as palpitations and sweating, and neuroglycopenic symptoms with a variety of neurological or psychiatric disturbances after fasting.

- Gastrinomas (20% of functioning pancreatic neuroendocrine neoplasms) cause Zollinger-Ellison syndrome, in which gastrin excess leads to hypersecretion of gastric acid, peptic ulcer disease, gastroesophageal reflux disease, and diarrhea ⁷. Pancreatic gastrinomas are usually sporadic, while duodenal gastrinomas (5 times more frequent) are typically small, and often multiple in MEN1-syndrome.

- Glucagonomas (3-4%) present with necrolytic migratory erythema, diabetes mellitus, weight loss, and anemia ⁸.
- VIPomas (< 3%) cause Verner-Morrison syndrome due to hypersecretion of VIP (a neuropeptide located in peptidergic neurons of the gut and pancreas), leading to watery diarrhea, hypokalemia, and achlorhydria ⁹.
- Somatostatinomas are rare, mostly located in the duodenum or periampullary area, and often associated with neurofibromatosis type 1. They cause a somatostatinoma syndrome in 2/3 of cases, with achloridria, cholelithiasis, mild diabetes, and steatorrhea due to the inhibitory effects of somatostatin on secretion and motility of the upper gastrointestinal tract ¹⁰.
- Rare (<1%) pancreatic carcinoids may secrete serotonin and other active amines and peptides, leading to carcinoid syndrome. This syndrome typically presents with episodic flushing, abdominal cramping, diarrhea, valvular heart disease and wheezing ¹¹.

Other rare pancreatic neuroendocrine neoplasms may secrete parathyroid hormone-related peptide (PTHrp), causing severe hypercalcemia with suppressed PTH levels. They may also release growth hormone-releasing hormone (GHRH) resulting in acromegaly, or ectopic adrenocorticotropic hormone (ACTH) leading to Cushing’s syndrome.

TNM Staging of pancreatic neuroendocrine neoplasms

Currently, there are two TNM staging systems for pancreatic neuroendocrine neoplasms, the European (ENETS) and the American system (AJCC, Table 2), who’s use and advantages are still debated. The ENETS system may offer benefits when applied to all pNETs and to the functional subgroup, while the AJCC system may be more practical for non-functioning pancreatic neuroendocrine neoplasms¹².

Due to the generally indolent behavior and slow growth of pancreatic neuroendocrine neoplasms, malignancy is defined only when local invasion or metastases occur. However, nearly 90% of pancreatic neuroendocrine neoplasms are low-grade (G1) or intermediate-grade (G2), and associated with a prolonged natural history, even when metastatic.

Over 35% of pancreatic neuroendocrine neoplasms have metastatic disease at diagnosis. Approximately 80% of metastases occur in the liver, with the liver being the only site in 50% of cases. The presence of liver metastases, the extent of secondary liver invasion, and the grading heterogeneity of metastases are crucial factors for assessing prognosis and choosing loco-regional treatment.

Diagnosis

Biomarkers

In functioning pancreatic neuroendocrine neoplasms, a specific hormone assay (in serum/plasma) may reveal inappropriate secretion of insulin, gastrin, glucagon, VIP, somatostatin, ACTH, serotonin (or excretion of urinary 5 hydroxy-indoleacetic acid). ¹³ In non-functioning pancreatic neuroendocrine neoplasms, changes in calcitonin, Pancreatic Polypeptide, NSE, and HCG alpha-subunit can be seen in some cases.

In insulinomas, the biochemical diagnosis is based on the evidence of hypoglycemic symptoms during a 72-hours fasting test with a serum glucose concentration of <50 mg/dL and elevated serum insulin of >3.0 U/ml.

In gastrinomas, the diagnosis is based on high levels of fasting serum gastrin (>100 pg/ml). A contemporary low gastric pH (< 2) rules out chronic atrophic gastritis and hypergastrinemia, due to acid suppression using proton pump inhibitors. Subsequently, in patients with Zollinger-Ellison syndrome, an intravenous secretin injection (2 U/kg body weight) results in a rise of serum gastrin within 10 minutes. In the other rare functioning pancreatic neuroendocrine neoplasms, a 3 to 5-fold increase of the specific hormone is commonly found, while a 10-fold increase raises suspicion of metastatic spread. Chromogranin A, a glycoprotein found in neuroendocrine cells, is currently the most used biomarker to monitor therapeutic response for neuroendocrine neoplasms. However, in case of localized disease or low metastatic burden, the sensitivity is low. Additionally, false-positive results are common in conditions such as chronic atrophic gastritis and with use of proton pump inhibitors, limiting its use in these patients. The NETest is an RNA-based assay that detects several circulating transcriptome signatures of pancreatic neuroendocrine neoplasms and outperformed other pNET biomarkers for prediction of tumor burden, disease progression, and response to therapy in a recent prospective comparative study ¹⁴.

Cross-sectional imaging

Conventional cross-sectional imaging ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) are critical diagnostic tools used for pancreatic neuroendocrine neoplasms localization, characterization, staging and biopsy. Additionally, functional imaging with the Somatostatin-Receptor Scintigraphy (Octreoscan®), or, more recently 68Gallium-DOTA-peptide Positron Emission Tomography (PET), can diagnose distant clinically unsuspected metastases. For high-grade pancreatic neuroendocrine neoplasms and pNECs, that have higher glucose metabolism and lower expression of somatostatin receptors, the 18F-FDG-PET is superior to 68Ga-DOTA-peptide PET for functional imaging. Cross-sectional and functional imaging are used in a complementary manner.

Multiphasic CT with intravenous contrast increases the diagnostic yield in pancreatic neuroendocrine neoplasms, which are generally hypervascular, with enhancement in the late arterial phase. For liver metastases detection, MRI is more sensitive, especially in the hepatic arterial phase and fast spin-echo T2 weighted images (T2WI). Hepatocellular phase-contrast agents can further improve metastases detection. MR diffusion-weighted imaging (DWI) is increasingly being used in the evaluation of pNENs, as they show diffusion restriction due to their high cellularity. Moreover, DWI may help in distinguish liver metastasis from hemangioma (both hyperintense on T2WI) ¹⁵. Recent studies ¹⁶ reported that 68Ga-DOTATOC PET/MRI was superior to 68Ga-DOTATOC PET/CT in detecting liver metastases and may be better in the evaluation of advanced cases.

Endoscopic ultrasound

Endoscopic ultrasound, potentially with complementary contrast enhancement or biopsy, offers the highest available imaging sensitivity for pancreatic neuroendocrine neoplasms. Fine needle aspiration and biopsy are sufficient for pre-operative diagnosis and grading of pancreatic neuroendocrine neoplasms. It is able to discriminate grade 3 NET or NEC with an accuracy over 90% ¹⁷.

Management and Treatment

Surgery

Surgical resection remains the only possible treatment for patients with localized functioning pancreatic neuroendocrine neoplasms without metastases. If patients, fit for surgery, with functioning pNETs are diagnosed with metastatic spread, the surgery option is still considered, with the aim to remove the primary tumor and peritumoral lymph nodes; resection or debulking of liver metastases is advisable to reduce tumor load and symptoms related to hormonal hypersecretion. Vascular resection of porto-mesenteric axis can be considered in case of curative intent.

There is general agreement that asymptomatic non-functioning pNETs <1 cm can be safely followed, taking into account their indolent behavior and extremely low metastatic potential. However, the management of asymptomatic pNETs between 1 and 2 cm is still controversial and North American guidelines differ from the European “watch and wait” recommendation. For these pNETs, the latter recommends individualized management based on the patient’s age, comorbidities, extent of needed surgery, tumor grade, and patient preference ¹⁸. On the other hand, in a recent study on resected pNETs <2 cm. ¹⁹, 26% had high-risk pathological factors (G2, microvascular invasion, or 6% of lymph-node metastases). For a pNET <2 cm, “a parenchyma-sparing procedure” is indicated (such as, enucleation, central pancreatectomy, duodenum-preserving pancreatic head resection, or short tail resection with spleen preservation) aiming for a better long-term quality of life due to preservation of pancreatic exocrine/endocrine functions ²⁰.

There is agreement that well-differentiated pNETs >2 cm should be resected with curative intent (including regional lymphadenectomy) in surgically fit patients, with standard left-side pancreatectomy or pancreatico-duodenectomy, depending on site of the lesion ¹⁸.

In oligometastatic disease (up to 3-5 lesions, <3 cm), curative approaches such as laparoscopic or percutaneous ablation using radiofrequency or microwave devices may be considered. Both methods deliver thermal energy to the target lesion, inducing coagulative necrosis.

Medical treatment

Somatostatin analogues (i.e., octreotide, lanreotide) are considered the first treatment of choice for functioning and non-functioning low-grade advanced pNETs (Ki67 <10%) with a positive expression of somatostatin receptors at 68Ga-PET. However, these do not cause tumor shrinkage, but only stabilize the tumor burden. In functioning advanced pNENs, hormonal and symptomatic control are required to improve survival and quality of life. In insulin-secreting tumors, diazoxide and diet control is required. In gastrinomas with ZES, high PPI dose is needed to control gastric acid secretion. Somatostatin analogues are very active to block hormone secretion (and related symptoms) in VIPoma and glucagonomas.

For low-grade pNETs who progress on somatostatin analogues, chemotherapy regimens (streptozotocin and 5-FU, or Capecitabine-Temozolomide) have limited effect, with 13 months of median progression-free survival at best ²¹. In addition, targeted therapies such as everolimus (mTOR inhibitor) or sunitinib (multi-receptor tyrosine kinase inhibitor) have been used, but these prolong overall survival with only 6-7 months.

Platinum-based therapy (cisplatin plus etoposide) is still standard of care for more aggressive G3 pNETs and NECs. Also, combination immunotherapy (Ipilimumab and Nivolumab) shows promising moderate clinical benefit, yet is not yet used in general clinical practice.

Peptide recepter radiotherapy

Peptide receptor radiotherapy (PRRT) is a promising treatment for advanced well-differentiated NETs, including those located in the pancreas. Intravenous injection of 177Lu-DOTATATE irradiates NET cells bearing somatostatin receptors directly, irrespective to the site of tumor cells. PRRT results in an objective response in 30-40% of cases and is able to stabilize NETs for a long period of time, with a median progression-free survival of 32.3 months and a median overall survival of 72.5 months (for NETs of different origin). The side effects of PRRT are mild, yet late myelodysplastic syndrome occurs in 5% of cases ²².

Liver-Directed Therapy for pNETs Metastases

When metastases are multiple, bilateral, and unresectable, strategies to improve life expectancy and quality of life, such as trans-arterial (chemo)-embolization (TAE/TACE) or selective internal radiation therapy, may be used to control tumor growth ²³.

Liver metastases are almost exclusively vascularized by the arterial hepatic system. Therefore, TAE and TACE effectively induce ischemic damage to NEN metastases while sparing the surrounding liver parenchyma. It can be applied palliatively in patients with G1-G2 pNETs that have progressed on somatostatin analogues. TACE combines chemotherapeutic agents with ischemic particles injected in the arterial vessels feeding the lesion(s). However, there is no clinical evidence supporting TACE over TAE. The procedure can be repeated every 4-8 weeks, treating one hepatic lobe per session. Liver involvement of >75%, impaired hepatic function, portal vein thrombosis and bilio-enteric anastomosis are contraindications. Post-embolization syndrome (fever, nausea or abdominal pain) occurs in most patients, but complications, such as a hepatic abscess or ischemic cholecystitis, occur in <10% of cases. Radiologic response is high (>90%), and last for at least 10 months.

Liver-only metastatic disease from pNETs are a potential indication for liver transplantation, but this is debated because of the high recurrence rate (60%), indolent behavior of pNETs, and organ shortage. However, results have improved in the last decade, with 5-year tumor-free survival rates up to 62% ²⁴. Following strict Milan criteria, only individuals aged <55 years with previously resected G1 pNETs, limited to the liver with <50% involvement, and stable for six months, are candidates for liver transplantation.

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