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Pancreatic neuroendocrine tumours are rare neoplasms arising from cells of the neuroendocrine system distributed throughout the pancreatic parenchyma. They form a biologically and clinically heterogeneous entity distinct from ductal adenocarcinoma in behaviour, prognosis and therapeutic approach. These cells, derived from the APUD system, can synthesise, store and secrete hormones and bioactive peptides, giving pancreatic neuroendocrine tumours great variability in clinical presentation. Histopathologically, these neoplasms include functioning forms, characterised by clinical syndromes related to hormonal hypersecretion, and non-functioning forms, which lack specific endocrine symptoms and are often diagnosed at a more advanced stage.

Pancreatic neuroendocrine tumours may arise in any part of the gland without a clear anatomical predilection and show a broad spectrum of biological aggressiveness, ranging from slowly growing well-differentiated lesions to high-grade poorly differentiated forms characterised by marked proliferation and rapid progression. Modern classification is based on the degree of differentiation and proliferative index, which reflect the tumour’s biological potential and guide clinical management. Unlike pancreatic adenocarcinoma, neuroendocrine tumours tend to grow expansively rather than infiltratively, but they may nevertheless metastasise, particularly to the liver.

The natural history of these neoplasms is extremely variable. Functioning forms may present early because of associated endocrine syndromes, whereas non-functioning tumours often remain silent until the size of the mass or the presence of metastases causes compressive or systemic symptoms. Diagnosis and staging require an integrated approach combining morphological and functional imaging, biochemical assessment and histological confirmation. Management is typically multidisciplinary and must take into account tumour biology, disease extent and the patient’s general condition.

The epidemiology of pancreatic neuroendocrine tumours is characterised by a low absolute incidence but a progressive increase in diagnoses over recent decades, largely attributable to improved diagnostic techniques and greater clinical awareness. Pancreatic neuroendocrine tumours account for a small proportion of all pancreatic neoplasms but represent one of the most important subgroups within gastroenteropancreatic neuroendocrine tumours. Incidence is generally estimated at a few cases per million people per year, with variation according to geographical area and the quality of cancer registries.

Demographically, these neoplasms predominantly affect adults, with peak incidence between the fifth and seventh decades of life, although some forms, particularly those associated with inherited genetic syndromes, may present at a younger age. Sex distribution is relatively balanced, with minor differences between men and women reported across series but no consistent clear predominance. Compared with pancreatic adenocarcinoma, overall prognosis is generally more favourable, particularly in well-differentiated, low-grade forms.

A substantial proportion of pancreatic neuroendocrine tumours arises sporadically, but several inherited genetic conditions confer a significantly increased risk. The most important is multiple endocrine neoplasia type 1, characterised by tumours of the parathyroid glands, pituitary and endocrine pancreas. In this setting, pancreatic neuroendocrine tumours are often multiple, small and either functioning or non-functioning. Other associated inherited syndromes include von Hippel–Lindau syndrome, neurofibromatosis type 1 and tuberous sclerosis, each with distinctive clinical and biological features.

Unlike pancreatic adenocarcinoma, environmental and behavioural risk factors for pancreatic neuroendocrine tumours are less clearly defined. There is no strong, consistent association with smoking or alcohol consumption, although some studies have suggested a possible role of metabolic factors and chronic inflammation in modulating risk. Associations with diabetes mellitus and obesity remain under investigation, and the available evidence does not support conclusions comparable to those established for ductal adenocarcinoma.

Biologically, pancreatic neuroendocrine tumours arise through molecular alterations affecting pathways essential to cell growth and differentiation. Mutations in genes regulating chromatin and cellular proliferation have been identified especially in sporadic well-differentiated forms, whereas poorly differentiated forms show distinct genetic profiles associated with more aggressive clinical behaviour. This molecular heterogeneity contributes to variability in clinical evolution and treatment response.

Taken together, these elements define an epidemiological picture in which pancreatic neuroendocrine tumours are rare but increasingly diagnosed neoplasms characterised by a broad spectrum of clinical and biological presentations. Distinguishing sporadic from inherited forms and functioning from non-functioning tumours is fundamental to appropriate risk stratification and the design of suitable diagnostic and therapeutic pathways.

There are no population screening programmes for pancreatic neuroendocrine tumours because of their rarity and the absence of simple, sufficiently accurate tests for large-scale use. In the general population, systematic screening would create a high risk of incidental findings and unjustified invasive diagnostic procedures, with an unfavourable cost–benefit ratio. Early identification therefore relies mainly on targeted clinical assessment and appropriate use of diagnostic methods in symptomatic individuals.

Selective surveillance is clearly indicated in individuals with high-risk inherited genetic syndromes, particularly multiple endocrine neoplasia type 1. In these patients, periodic pancreatic monitoring is an integral part of clinical management and begins early, often at a young age. The aim is to detect small neuroendocrine lesions before they acquire aggressive behaviour or cause endocrine or metastatic complications.

Surveillance methods include pancreatic endoscopic ultrasonography and magnetic resonance imaging, which permit detailed assessment of the pancreatic parenchyma and ducts without exposure to ionising radiation. Endoscopic ultrasonography in particular has high sensitivity for small lesions and permits cytological or histological sampling when required. The choice and frequency of examinations are tailored to the individual risk profile and lesion evolution over time.

In patients with already diagnosed pancreatic neuroendocrine tumours, surveillance has a central role in follow-up, especially for slowly growing well-differentiated forms. Periodic monitoring assesses disease stability, possible local or metastatic progression and the development of new lesions, guiding therapeutic decisions and the timing of intervention. Integration of morphological and functional imaging is particularly important in this context.

Emerging approaches to improve early identification and monitoring of pancreatic neuroendocrine tumours are under study, including circulating biomarkers and advanced molecular imaging techniques. These tools have not yet achieved an established role in routine clinical practice and remain largely confined to research settings or highly specialised centres.

Overall, the absence of population screening makes targeted surveillance in high-risk groups and structured follow-up in affected patients essential. The effectiveness of these strategies depends on correct subject selection, appropriate use of diagnostic methods and integration of monitoring into multidisciplinary clinical pathways.

Pancreatic neuroendocrine tumours arise from neuroendocrine cells of the endocrine pancreas, located predominantly within the islets of Langerhans. These cells are physiologically responsible for producing hormones and regulatory peptides and possess marked secretory capacity and high functional plasticity. Neoplastic transformation occurs through a gradual loss of proliferative control and dysregulation of differentiation programmes within a biological setting distinct from pancreatic ductal adenocarcinoma.

Pathogenetically, pancreatic neuroendocrine tumours may arise sporadically or in the context of inherited genetic syndromes, including multiple endocrine neoplasia type 1, von Hippel–Lindau syndrome, neurofibromatosis type 1 and tuberous sclerosis. In these settings, germline mutations cause early disruption of cellular-growth control mechanisms, predisposing to multifocal lesions that often present earlier than sporadic forms.

From a genetic perspective, pancreatic neuroendocrine tumours have a characteristic molecular profile distinct from that of exocrine pancreatic neoplasms. Inactivating mutations of MEN1, which encodes menin, are among the most frequent alterations and have a central role in dysregulation of gene transcription, chromatin stability and the DNA-damage response. Alterations in genes involved in regulating cell growth and metabolism, including DAXX, ATRX, TSC2 and PTEN, further contribute to pathogenesis through effects on the mTOR pathway and mechanisms controlling cellular homeostasis.

A distinctive feature of a substantial proportion of pancreatic neuroendocrine tumours is the presence of telomere alterations and alternative telomere-lengthening mechanisms, frequently associated with DAXX and ATRX mutations. These changes promote replicative stability of neoplastic cells and contribute to their ability to sustain prolonged proliferation. Compared with ductal adenocarcinoma, global genomic instability is generally less marked, consistently with often more indolent biological behaviour.

Epigenetic modifications have an important role in determining the neuroendocrine phenotype. Alterations in DNA methylation and chromatin structure affect expression of genes involved in hormonal secretion, proliferation and cellular differentiation. Dysregulation of specific microRNAs contributes to modulation of growth circuits and invasive capacity while, in many cases, a high degree of differentiation is preserved.

The tumour microenvironment of pancreatic neuroendocrine tumours is generally less desmoplastic than that of ductal adenocarcinoma but is richly vascularised. Angiogenesis is a central biological feature, supported by expression of factors such as VEGF and close interaction between neoplastic cells and the endothelial compartment. This feature explains the high uptake of tracers on functional imaging and sensitivity to antiangiogenic therapies in specific clinical settings.

From an immunological perspective, pancreatic neuroendocrine tumours show variable immune infiltration, generally less intense than that observed in other solid neoplasms. PD-L1 expression is usually low, and the limited mutational burden is associated with low immunogenicity. Nevertheless, interaction with innate immune cells and the stromal microenvironment contributes to tumour progression and escape from immune-control mechanisms.

According to biological and functional characteristics, pancreatic neuroendocrine tumours are classified as:

• functioning tumours, characterised by clinically relevant secretion of hormones such as insulin, gastrin, glucagon or VIP;
• non-functioning tumours, without a clinically evident hormonal syndrome and often diagnosed at a more advanced stage;
• high-grade neuroendocrine neoplasms, which are biologically more aggressive, with marked proliferation and loss of differentiation.

This classification reflects genuine biological and clinical heterogeneity with significant prognostic consequences.

Histologically, well-differentiated pancreatic neuroendocrine neoplasms show organoid growth with trabecular, insular or glandular patterns, uniform cells with finely granular chromatin and limited pleomorphism. Mitotic count and the Ki-67 index permit stratification into different proliferative grades. Poorly differentiated forms instead show disorganised architecture, a high mitotic index, necrosis and highly aggressive behaviour.

Immunohistochemistry is fundamental to characterisation: chromogranin A and synaptophysin confirm neuroendocrine differentiation, whereas Ki-67 is the principal parameter for prognostic classification. Assessment of vascular and perineural invasion contributes to defining the neoplasm’s infiltrative capacity.

Overall, pancreatic neuroendocrine tumours are a heterogeneous group of neoplasms characterised by distinct biology, often slow-growing but potentially progressive, determined by the interaction between specific genetic alterations, epigenetic regulation, rich angiogenesis and modulation of the local microenvironment.

The clinical manifestations of pancreatic neuroendocrine tumours are extremely heterogeneous and depend on the neoplasm’s ability to produce biologically active hormones, the size of the lesion and the local or systemic extent of disease. A substantial proportion of tumours, particularly non-functioning tumours, may remain asymptomatic for a long time and are identified incidentally during imaging performed for other indications.

In functioning tumours, symptoms are dominated by the hormone-hypersecretion syndrome. Insulinomas present with recurrent episodes of hypoglycaemia, characterised by sweating, tremor, confusion and, in the most severe cases, loss of consciousness. Gastrinomas cause Zollinger–Ellison syndrome, with acid hypersecretion, recurrent peptic ulcers, epigastric pain and diarrhoea. Glucagonomas are associated with diabetes, weight loss and a characteristic skin rash, whereas VIPomas cause profuse secretory diarrhoea, dehydration and electrolyte abnormalities.

Non-functioning tumours, by contrast, tend to present with symptoms related to the tumour mass. Dull, persistent abdominal pain, located in the epigastrium or hypochondrium, is a common finding and reflects distension of the pancreatic capsule or infiltration of adjacent structures. Weight loss and asthenia may occur, particularly in larger lesions or advanced disease.

As the tumour increases in size, compression of the biliary tract may cause jaundice, more commonly in tumours located in the pancreatic head. In tumours of the body and tail, clinical presentation is often later and dominated by pain and non-specific systemic symptoms. Changes in bowel habits, nausea and early satiety may occur because of compression of adjacent gastrointestinal structures.

Clinical presentation varies according to functional type:

• insulinoma: recurrent hypoglycaemia, neuroglycopenia and compensatory weight gain;
• gastrinoma: multiple peptic ulcers, epigastric pain and diarrhoea;
• non-functioning tumours: abdominal pain, a palpable mass, weight loss and late diagnosis.

Disease progression may lead to metastatic spread, most commonly involving the liver. Hepatic metastases may be clinically silent or present with hepatomegaly, right upper-quadrant pain and impaired liver function. Functionally active metastases may intensify the hormonal syndrome, making clinical control more difficult.

At an advanced stage, signs of exocrine pancreatic insufficiency may develop, with steatorrhoea, malabsorption and further weight loss. The systemic impact of disease often results in marked asthenia and reduced physical performance despite relatively slow tumour growth.

On physical examination, findings may be subtle or absent in the early stages. In more advanced disease, hepatomegaly, jaundice, abdominal tenderness and signs of nutritional impairment may be detected. The overall clinical picture is that of a neoplasm with a variable course, often indolent but potentially progressive, in which persistent endocrine or abdominal symptoms should always prompt targeted diagnostic investigation.

The diagnostic work-up for pancreatic neuroendocrine tumours begins with clinical suspicion and proceeds through a sequence of investigations aimed first at morphological confirmation of the neoplasm, then at functional and biological characterisation and finally at defining disease extent, without yet introducing formal staging. Clinical suspicion may arise in heterogeneous ways, reflecting the variable nature of these neoplasms. In functioning tumours, symptoms are related to hormone hypersecretion and include recurrent hypoglycaemia, refractory peptic-ulcer syndromes, secretory diarrhoea, flushing, bronchospasm or electrolyte abnormalities. In the more common non-functioning tumours, onset is often late and non-specific, with abdominal pain, weight loss, jaundice due to biliary compression or an incidental finding on imaging performed for other indications. In this setting, the first clinical objective is to recognise a suggestive presentation and refer the patient for highly sensitive investigations.

Laboratory tests provide essential initial support, particularly in functioning tumours. Measurement of specific hormones and peptides, such as insulin, gastrin, glucagon, VIP or somatostatin, is guided by clinical suspicion and can document the hypersecretion responsible for symptoms. Chromogranin A may be elevated and is a general marker of neuroendocrine disease, although its specificity is limited. Biochemical findings must be interpreted in the clinical context and cannot establish a definitive diagnosis on their own.

Imaging is a central component of diagnostic assessment. Contrast-enhanced computed tomography performed with a pancreatic protocol can identify the primary lesion, define its size and assess possible secondary sites. Pancreatic neuroendocrine tumours typically appear as hypervascular lesions during the arterial phases, with characteristics that differ from ductal adenocarcinoma. Magnetic resonance imaging offers high sensitivity, particularly for small lesions and for assessing hepatic metastases, which are a frequent site of spread.

Endoscopic ultrasonography (EUS) has a key role in diagnosing pancreatic neuroendocrine tumours because its high spatial resolution permits detection of lesions only a few millimetres in size. During EUS, EUS-guided fine-needle aspiration or core-needle biopsy may be performed, providing adequate cytological or histological material for definitive characterisation. EUS is particularly indicated when imaging is inconclusive or histological confirmation is required before treatment.

Histopathological analysis permits the definitive diagnosis of a neuroendocrine tumour. Histology shows a proliferation of uniform cells arranged in nests, trabeculae or glandular structures, with finely granular chromatin and moderately abundant cytoplasm. Immunohistochemistry demonstrates expression of neuroendocrine markers such as chromogranin A and synaptophysin, confirming the nature of the neoplasm. A crucial element is assessment of the Ki-67 proliferation index, expressed as the percentage of positive cells, which permits classification of the tumour into different grades of biological aggressiveness. The pathologist also determines the presence of necrosis and vascular or perineural invasion.

According to the principal international guidelines, a minimum core of clinical, radiological and pathological information must be available before a diagnosis of pancreatic neuroendocrine tumour can be considered established and treatment decisions made; these elements are not formal “diagnostic criteria” but constitute the essential requirements for a reliable diagnosis:

Elements required to establish a diagnosis of pancreatic neuroendocrine tumour

• Identification of a suspicious pancreatic lesion by cross-sectional imaging.
• Consistency between the clinical and biochemical presentation and radiological findings.
• Histological or cytological confirmation of neuroendocrine differentiation by EUS-guided sampling.
• Immunohistochemical documentation with neuroendocrine markers.
• Assessment of the Ki-67 proliferation index to define grade.

The differential diagnosis must include pancreatic adenocarcinoma, acinar neoplasms, cystic lesions with a solid component and pancreatic metastases from other primary sites. The combination of imaging pattern, histological features and immunohistochemical profile permits a clear distinction in most cases. In functioning tumours, non-neoplastic conditions responsible for hormone hypersecretion must also be considered and excluded through appropriate biochemical assessment.

Once the diagnosis has been confirmed, investigations focus on assessing disease extent. In addition to CT and MRI, functional imaging with PET using somatostatin-receptor tracers can identify sites of disease expressing these receptors and assess suitability for targeted therapies. 18F-FDG PET may be useful in higher-grade forms to identify biologically more aggressive areas. In selected cases, endoscopic or interventional procedures are used for symptomatic or therapeutic purposes rather than as primary diagnostic procedures.

In summary, the diagnostic assessment of pancreatic neuroendocrine tumours follows a practical sequence: clinical suspicion; targeted biochemical assessment; CT and MRI; endoscopic ultrasonography with sampling; histological confirmation and biological classification; and then assessment of disease extent by morphological and functional imaging.

Staging of pancreatic neuroendocrine tumours integrates the anatomical and biological information obtained during diagnostic assessment and permits a standardised description of disease extent while also providing prognostic information. The international reference system is the TNM classification proposed by ENETS and adopted by the AJCC/UICC, which considers the size and invasiveness of the primary tumour, lymph-node involvement and the presence of distant metastases.

Clinical cTNM staging is based on integration of findings from computed tomography, magnetic resonance imaging and functional imaging. CT and MRI permit assessment of tumour size, relationships with vascular structures and the presence of metastases, particularly hepatic metastases. Receptor imaging contributes to more sensitive definition of disease extent, especially in well-differentiated forms.

In pancreatic neuroendocrine tumours, prognosis is determined by a combination of anatomical and biological factors. The TNM system describes the spatial extent of disease, but the histological grade defined by the Ki-67 index is a prognostic determinant of primary importance. Well-differentiated, low-grade tumours often follow an indolent course, whereas high-grade forms show aggressive behaviour and rapid progression.

Conceptually, the main stage groups may be summarised as follows:

Main stage groups in pancreatic neuroendocrine tumours

• Stage I: a small tumour confined to the pancreas, without lymph-node or distant metastases.
• Stage II: a more locally extensive tumour or initial involvement of peripancreatic tissues, without distant metastases.
• Stage III: regional lymph-node metastases or advanced local extension.
• Stage IV: distant metastases, most commonly involving the liver.

When a surgical specimen is available, pathological pTNM staging permits more accurate prognostic assessment through direct evaluation of tumour size, the number of lymph nodes examined and involved, and the presence of vascular or perineural invasion. Complete resection of the primary disease and selected metastases is associated with a significant improvement in outcome in well-differentiated forms.

Survival curves show marked heterogeneity. Well-differentiated, low-grade tumours may be associated with prolonged survival even in the presence of metastatic disease, whereas high-grade forms have a distinctly poorer prognosis and shorter median survival. Multiple hepatic metastases and a high proliferation index are associated with unfavourable outcomes.

In addition to TNM stage and grade, several additional prognostic factors contribute to individual risk. Important tumour-related factors include hepatic metastatic burden and tumour growth documented over time. Patient-related factors, including performance status, nutritional status and comorbidities, influence treatment tolerance and overall prognosis. Somatostatin-receptor expression is predictive of response to specific therapeutic strategies.

Overall, staging of pancreatic neuroendocrine tumours is an integrated process combining anatomical extent and biological behaviour. Prognosis is generally favourable in well-differentiated, localised forms, whereas in high-grade disease or extensive metastatic spread the outcome remains less favourable and is influenced by response to systemic therapies.

Treatment of pancreatic neuroendocrine tumours is based on a multimodal and highly individualised approach, reflecting the broad biological and clinical heterogeneity of these neoplasms. Therapeutic strategies are defined within an experienced multidisciplinary team and depend on the degree of differentiation, proliferation index, disease stage, hormonal function, tumour burden, growth over time and the patient’s general condition. Unlike pancreatic adenocarcinoma, treatment goals may range from curative intent to long-term disease control.

In localised, well-differentiated tumours, surgery is the treatment of choice with curative intent. The procedure depends on the lesion’s location and size: enucleation may be considered for small peripheral tumours located away from the main pancreatic duct, whereas pancreaticoduodenectomy or distal pancreatectomy is indicated for larger or centrally located lesions. The objective is complete resection with negative margins, together with adequate lymphadenectomy, which is essential for correct staging.

In patients with low-aggressiveness metastatic disease, particularly synchronous or metachronous hepatic metastases, surgery may retain a selective role. In carefully selected cases, resection of the primary tumour and metastases, or debulking procedures, may improve symptom control and, in some series, prolong survival. The decision must balance disease extent, growth rate and operative risk.

Somatostatin analogues are a cornerstone of systemic treatment for well-differentiated pancreatic neuroendocrine tumours. Octreotide and lanreotide are used both to control hormonal symptoms in functioning forms and for their antiproliferative effect, which has also been demonstrated in slowly growing non-functioning neoplasms. These drugs are often used as first-line treatment in indolent metastatic disease.

Targeted therapies are available for patients with disease progression or more rapidly growing tumours. The mTOR inhibitor everolimus and the tyrosine-kinase inhibitor sunitinib have demonstrated benefit in disease control and are used in advanced, well-differentiated tumours. Selection among the available options depends on toxicity profile, comorbidities and the tumour’s biological characteristics.

Cytotoxic chemotherapy is indicated mainly in intermediate-grade pancreatic neuroendocrine tumours or in well-differentiated tumours with a high tumour burden or rapid progression. Regimens based on temozolomide combined with capecitabine are frequently used and may induce substantial responses. More intensive regimens, including platinum-based combinations, are reserved for more aggressive forms.

In poorly differentiated neuroendocrine tumours with a high proliferation index, biological behaviour resembles that of neuroendocrine carcinomas. In this context, the reference treatment is systemic chemotherapy with platinum- and etoposide-based regimens, mainly with palliative intent because of the high aggressiveness of the disease.

An expanding role is played by peptide receptor radionuclide therapy using radionuclides bound to somatostatin analogues in tumours expressing the relevant receptors on functional imaging. This strategy can provide prolonged disease control in selected patients with advanced, progressive disease.

Liver-directed locoregional therapies, such as embolisation, chemoembolisation or radioembolisation, may be used to control dominant hepatic metastases, particularly when hormonal symptoms are difficult to control or progression is predominantly hepatic.

At every stage of disease, symptomatic and nutritional support is essential. In functioning tumours, control of hormonal syndromes requires careful monitoring and continuous therapeutic adjustment. Early involvement of supportive care contributes substantially to quality of life and continuity of treatment.

Follow-up and post-treatment surveillance of pancreatic neuroendocrine tumours must reflect the often chronic nature of these neoplasms, which are characterised by a prolonged course and possible slow progression over time. The principal objectives are early identification of recurrence or progression, monitoring of treatment sequelae and control of hormonal syndromes.

In patients who have undergone surgical resection with curative intent, follow-up is aimed at detecting local or metastatic recurrence. Clinical and radiological assessments are generally scheduled at regular intervals, with computed tomography or magnetic resonance imaging as the reference examinations. The frequency of assessment depends on the degree of differentiation, initial stage and prognostic factors.

In patients with advanced disease receiving systemic treatment, follow-up largely coincides with monitoring of therapeutic response. Imaging is used to assess stability, response or progression, recognising that dimensional changes may be slow and that prolonged stability often constitutes a clinically relevant result.

Biochemical markers have an important supporting role in clinical monitoring. Their value must be interpreted within the overall clinical and radiological context, avoiding decisions based solely on isolated changes.

In functioning forms, follow-up includes systematic assessment of symptoms related to hormonal hyperproduction and adjustment of treatment with somatostatin analogues or other specific drugs. Effective control of the hormonal syndrome is a central and often continuous objective.

Follow-up also includes management of chronic treatment toxicities, including metabolic, haematological and renal effects, as well as endocrine sequelae after pancreatic surgery, such as diabetes and exocrine pancreatic insufficiency. Nutritional monitoring is essential to prevent weight loss and sarcopenia.

Follow-up is generally prolonged, often extending over many years because late recurrence is possible. In patients with stable or slowly progressive disease, follow-up is continuous and aimed at preserving quality of life and promptly modifying therapeutic strategies if biological behaviour changes.

In summary, follow-up of pancreatic neuroendocrine tumours is a dynamic, long-term process that integrates oncological surveillance, endocrine control and management of sequelae and requires a coordinated, flexible specialist approach.

Long-term quality-of-life considerations are a central component of the clinical management of pancreatic neuroendocrine tumours because these neoplasms are often chronic and a substantial proportion of patients experience prolonged survival. Even when disease is stable or controlled, functional, metabolic and psychological outcomes may significantly affect daily life, making structured and continuous quality-of-life monitoring necessary.

A fundamental domain is endocrine and metabolic function. In functioning neuroendocrine tumours, persistent or recurrent hormonal secretion may cause chronic symptoms such as hypoglycaemia, diarrhoea, flushing or electrolyte disturbances, affecting patient autonomy and safety. Patients who have undergone pancreatic resection may also develop pancreatogenic diabetes and glycaemic instability, requiring long-term lifestyle adjustment and specialist metabolic follow-up.

Digestive and pancreatic exocrine function substantially affects quality of life, particularly after extensive surgery. Exocrine pancreatic insufficiency may present with steatorrhoea, chronic diarrhoea and malabsorption, resulting in weight loss and fatigue. Enzyme replacement and individualised nutritional support are key elements in maintaining long-term wellbeing.

Nutrition and body composition are crucial determinants of quality of life. Loss of muscle mass, malnutrition and micronutrient deficiencies may develop progressively, particularly in patients receiving prolonged systemic treatment or affected by hormone-hypersecretion syndromes. Periodic monitoring of body composition and nutritional intake helps preserve functional capacity and autonomy.

The chronic treatment burden has a significant impact on daily life. Long-term treatment with somatostatin analogues or targeted therapies may be associated with persistent adverse effects, including gastrointestinal disorders, fatigue and metabolic abnormalities, requiring continuous balancing of disease control against tolerability.

The psychological and psychosocial domain is also important, particularly because of uncertainty associated with a disease course that is often indolent but unpredictable. Anxiety, emotional distress and difficulty with long-term planning may compromise psychological wellbeing and social relationships. Structured psychological support and clear, continuous communication with the treating team promote better adaptation to a chronic condition.

Overall, long-term quality of life in pancreatic neuroendocrine tumours depends on the healthcare system’s ability to provide integrated care combining oncological control with management of endocrine, digestive, nutritional and psychological sequelae. In this context, quality of life is a clinical outcome of primary importance and should be considered alongside indicators of disease control and survival.

Complications of pancreatic neuroendocrine tumours arise from the interaction between the biological behaviour of the neoplasm, hormone hypersecretion and surgical and systemic treatments, creating a complex clinical picture that requires long-term multidisciplinary management. Even in slowly growing forms, complications may have a substantial impact on quality of life and functional prognosis.

Local progression of the tumour may cause persistent abdominal pain, compression of the biliary tract or duodenum and worsening digestive symptoms. Infiltration of the retroperitoneal nerve plexuses is a frequent cause of chronic pain that may be difficult to control. In metastatic disease, hepatic involvement may lead to progressive liver failure and deterioration of general condition.

Complications related to hormone hypersecretion are a distinctive feature of functioning neuroendocrine tumours. Severe recurrent hypoglycaemia, profuse diarrhoea, electrolyte imbalances and hormone-excess syndromes may cause acute, potentially life-threatening events and require continuous pharmacological control and close monitoring.

Pancreatic surgery is associated with a non-negligible risk of complications. Postoperative pancreatic fistula, intra-abdominal infections, haemorrhage and delayed gastric emptying are the principal causes of morbidity. In the long term, exocrine and endocrine pancreatic insufficiency is a frequent sequela with a substantial impact on quality of life.

Systemic therapies, including somatostatin analogues, targeted therapies and radionuclide treatments, may induce acute and cumulative toxicity. Gastrointestinal disturbances, cholelithiasis, metabolic abnormalities, cytopenias and chronic fatigue are among the most common complications and may limit adherence to prolonged treatment.

Interventional procedures, such as hepatic embolisation or other locoregional techniques, carry specific risks including post-procedural pain, post-embolisation syndrome, transient liver failure and infections. Although generally manageable, these complications require careful patient selection and dedicated post-procedural monitoring.

Systemically, cachexia, infections and thromboembolic events may complicate the clinical course, particularly in advanced stages or in patients receiving multiple treatments. Progressive functional decline necessitates a comprehensive approach that integrates symptom control, nutritional support and, when indicated, palliative care at an early stage.

Management of complications is based on structured prevention, including endocrine and nutritional monitoring, surveillance of treatment toxicities, pain control and early recognition of signs of progression or hormone hypersecretion. Integration of multidisciplinary expertise reduces the severity of adverse events, improves quality of life and optimises long-term continuity of care.