Pancreatic Neuroendocrine Tumors

Etiology

Although the exact etiology of pNETs is not yet fully understood, several risk factors have been identified as associated with the pathogenesis of pNETs.

Pancreatic Neuroendocrine Tumor Risk Factors

Approximately 10% of pNETs are associated with hereditary syndromes, most notably MEN1, which is caused by a mutation in the MEN1 gene that encodes the tumor suppressor protein menin. Individuals with MEN1 have an increased risk of developing tumors in the parathyroid glands, pituitary gland, and pancreatic islet cells. Other genetic conditions linked to pNETs include von Hippel-Lindau disease, neurofibromatosis type 1, and tuberous sclerosis complex.[1]

Beyond hereditary predisposition, sporadic pNETs are often due to somatic mutations. Mutations in genes, eg, MEN1, DAXX, and ATRX have been identified in pNETs, suggesting their involvement in tumorigenesis by altering remodeling and epigenetic regulation.[2][3]

Environmental and lifestyle factors may also contribute to the development of pNETs. Smoking and heavy alcohol consumption might increase the risk of these tumors. Additionally, a family history of cancer or the presence of diabetes has been associated with a higher incidence of pNETs. However, further research is needed to elucidate these associations.[4]

Epidemiology

A pNET is considered a rare tumor, accounting for approximately 1% to 2% of all pancreatic neoplasms and 7% of neuroendocrine tumors overall.[5][6] The annual incidence of pNETS is estimated to be up to 1 in 100,000 individuals. However, their incidence has been rising over the last several decades, likely due to increased awareness and improved diagnostic techniques.[6][7][8]

The incidence of pNETs is slightly higher in men than in women. They are typically diagnosed in the fifth to seventh decades of life, with a median age at diagnosis of 55 to 60 years. However, patients with hereditary syndromes, eg, MEN1, may present at a younger age.[8][9][10]

Functional Versus Nonfunctional Tumors

A pNET can be classified as a functional (hormone-secreting) or nonfunctional tumor:

• Nonfunctional pNETs: These types of pNETs comprise 60% to 90% of cases and often present late with vague symptoms or are detected incidentally
• Functional pNETs: These types of pNETs, eg, insulinomas, gastrinomas, glucagonomas, VIPomas, and somatostatinomas, typically present earlier due to hormone-related symptoms. Insulinomas are the most common functional pNET.[8]

Pathophysiology

A pNET arises from the hormone-producing islet cells of the pancreas and exhibits a diverse pathophysiology based on its ability to secrete bioactive substances. The molecular mechanisms underlying the development of pNET involve genetic mutations that affect tumor suppressor genes, chromatin remodeling, and cellular proliferation pathways. Common mutations include alterations in genes related to MEN1, DAXX, ATRX, and the mTOR pathway, leading to dysregulated cell growth and differentiation.[3][11]

Functional Pancreatic Neuroendocrine Tumors

Functional pNETs actively secrete hormones, causing the following distinct clinical syndromes:

1. Insulinomas: The most common type; results from excessive insulin secretion, leading to recurrent episodes of hypoglycemia.
2. Gastrinomas: These tumors cause Zollinger-Ellison syndrome (ZES) due to excess gastrin, resulting in peptic ulcers and severe acid hypersecretion.
3. Glucagonomas: Excessive glucagon production leads to diabetes, weight loss, and necrolytic migratory erythema.
4. VIPomas: These tumors secrete vasoactive intestinal peptide (VIP), causing severe watery diarrhea, hypokalemia, and dehydration.
5. Somatostatinomas: Secretes excess somatostatin, leading to diabetes, hypochlorhydria, gallstones, and steatorrhea.

These tumors are often small and diagnosed earlier due to their pronounced clinical symptoms.[7][8]

Nonfunctional Pancreatic Neuroendocrine Tumors

Nonfunctional pNETs, which constitute 60% to 90% of cases, do not produce clinically significant hormone levels and typically present with nonspecific symptoms, eg, abdominal pain, weight loss, or mass effects leading to biliary or gastric obstruction. Due to their silent nature, these tumors are often diagnosed at an advanced stage. Molecularly, they share genetic alterations with functional pNETs, particularly in MEN1, DAXX, and ATRX, but do not exhibit hormone overproduction. Higher tumor grade and proliferation indices, such as Ki-67, correlate with increased aggressiveness and metastatic potential.[11][8]

Histopathology

Gross Histological Examination of Pancreatic Neuroendocrine Tumors

Grossly, pNETs are typically well-circumscribed, solid, and tan to yellow masses with a smooth or lobulated surface. The cut surface may appear homogeneous, although larger lesions can show areas of hemorrhage, cystic degeneration, necrosis, or calcification. These tumors are generally hypervascular, and some may compress adjacent ducts or vessels without direct invasion.

Pancreatic Neuroendocrine Tumors Functional Subtypes

The anatomical location within the pancreas often correlates with the tumor's functional subtype, which is discussed in more detail in individual activities on functional pNETs. Generally, insulinomas are the most common functional pNETs, are usually <2 cm in size, and tend to arise in the pancreatic body or tail. However, they can occur anywhere in the pancreas. Because they secrete insulin, they are often diagnosed early due to symptomatic hypoglycemia.

Gastrinomas frequently arise in the so-called "gastrinoma triangle," with the majority located in the duodenum, followed by the pancreatic head. Gastrinomas tend to be firm, solid, and gray-white on cut section, sometimes showing fibrosis or necrosis due to their more aggressive nature.

Somatostatinomas are rare tumors that are often larger at diagnosis and are commonly found in the pancreatic head or occasionally in the duodenum. Somatostatinomas may exhibit calcifications or central necrosis, especially when they are large or malignant.

Glucagonomas typically arise in the distal pancreas (body and tail) and are often large (≥4 cm) at the time of diagnosis, due to their relatively nonspecific early symptoms. On gross inspection, they may appear solid and fleshy, with areas of hemorrhage or necrosis if the disease is advanced.

VIPomas are rare tumors that usually arise in the pancreatic tail and tend to be larger at diagnosis (>3 cm), partly due to delayed symptom recognition. Grossly, they are soft, tan-pink masses, often with cystic degeneration or hemorrhage. Like glucagonomas, VIPomas are frequently metastatic at presentation, especially to the liver and lymph nodes.[12]

Overall, pNETs are generally composed of well-differentiated neuroendocrine cells arranged in nested, trabecular, or solid growth patterns, with uniform round nuclei, finely stippled "salt-and-pepper" chromatin, and moderate eosinophilic cytoplasm.[13] Immunohistochemically, pNETs express neuroendocrine markers, eg, chromogranin A, synaptophysin, and CD56, while Ki-67 and mitotic count are used for tumor grading. Low-grade (G1) and intermediate-grade (G2) pNETs demonstrate <20% Ki-67 proliferation, whereas high-grade (G3) tumors exhibit more aggressive features with increased mitotic activity. Necrosis, vascular invasion, and a high Ki-67 index are indicators of poor prognosis, distinguishing well-differentiated pNETs from highly aggressive neuroendocrine carcinomas.[14][15]

Pancreatic Neuroendocrine Tumor Grading

Grading is determined per the World Health Organization (WHO) criteria, which integrate proliferative indices—specifically the Ki-67 labeling index and mitotic count—with the degree of cellular differentiation. Neuroendocrine tumors are stratified into 3 the following grades based on mitotic rate and Ki-67 index:

• Grade 1: Low-grade, well-differentiated endocrine tumors exhibiting benign or uncertain behavior at diagnosis, characterized by a mitotic count of <2 per 10 high-power fields (HPF) and a Ki-67 index of <3%.
• Grade 2: Low-grade, well-differentiated endocrine tumors with intermediate proliferative activity, evidenced by a mitotic count of 2 to 20 per 10 HPF and a Ki-67 index of 3% to 20%.
• Grade 3: High-grade, poorly differentiated neuroendocrine carcinomas with aggressive clinical behavior, defined by a mitotic count of >20 per 10 HPF and a Ki-67 index of >20%.

This grading system (see Table. World Health Organization 2022 Classification of Neuroendocrine Tumors) provides critical prognostic information and guides therapeutic decision-making in the management of pNETs.[16][17]

Table: World Health Organization 2022 Classification of Neuroendocrine Tumors

History and Physical

Patients with pNETs can present with a wide range of clinical manifestations depending on whether they are functional (hormone-secreting) or nonfunctional (hormone-inactive). A thorough history and physical examination are essential for early recognition.

Functional Pancreatic Neuroendocrine Tumors

Functional pNETs secrete bioactive hormones, leading to distinct clinical syndromes:

• Insulinoma: History of episodic hypoglycemia (Whipple’s triad) with confusion, palpitations, diaphoresis, and relief with glucose intake. Physical exam may reveal altered mental status or adrenergic signs.
• Gastrinoma (Zollinger-Ellison Syndrome): Presents with severe peptic ulcers, gastroesophageal reflux, and diarrhea due to excessive acid secretion. Patients may have epigastric tenderness on exam.
• Glucagonoma: Causes diabetes, weight loss, and necrolytic migratory erythema, a characteristic erythematous, blistering rash often found in intertriginous areas.
• VIPoma (Verner-Morrison Syndrome): Patients present with profuse watery diarrhea, dehydration, hypokalemia, and achlorhydria (WDHA syndrome). An exam may reveal signs of volume depletion, such as hypotension or dry mucous membranes.
• Somatostatinoma: Causes diabetes, gallstones, steatorrhea, and achlorhydria. Physical exam may reveal cachexia, jaundice, or signs of fat malabsorption.

Nonfunctional Pancreatic Neuroendocrine Tumors

Nonfunctional pNETs, which make up 60% to 90% of cases, do not secrete clinically significant hormones and are often asymptomatic until they reach a large size or metastasize. History may include abdominal pain, weight loss, early satiety, or jaundice. On physical examination, the following findings may be noted:

• Large tumors may present as a palpable epigastric mass.
• Biliary obstruction can cause jaundice, hepatomegaly, or pruritus.
• Metastatic disease may manifest with hepatomegaly (liver metastases), ascites (peritoneal spread), or lymphadenopathy.

Evaluation

The evaluation of pNETs involves a comprehensive approach, including laboratory assessments and radiographic analyses.[18][19]

Laboratory Tests

Laboratory studies that are used to evaluate pNETs include:

• Biochemical Markers: Measurement of serum chromogranin A is commonly performed, as elevated levels may indicate the presence of pNETs. However, serum chromogranin A levels can be influenced by various factors and falsely elevated in chronic proton pump inhibitor use, renal insufficiency, or atrophic gastritis. Therefore, biochemical markers are a useful screening test but have low specificity when diagnosing pNETs.
• Hormonal Assays: For functional pNETs, specific hormone levels should be assessed based on clinical presentation.
• Insulinomas: Laboratory findings typically show elevated insulin, C-peptide, and proinsulin levels despite hypoglycemia (glucose <55 mg/dL), which is part of Whipple's Triad. A fasting insulin level above 3 μU/mL, a C-peptide level greater than 0.6 ng/mL, and proinsulin exceeding 5 pmol/L in the setting of low blood glucose strongly suggest insulinoma, differentiating it from exogenous insulin administration.
• Gastrinomas: Fasting serum gastrin levels exceeding 1000 pg/mL are highly diagnostic. If levels fall within an intermediate range (100–1000 pg/mL), a secretin stimulation test can be performed, where a paradoxical rise in gastrin levels by more than 200 pg/mL confirms the diagnosis. Additionally, a low gastric pH (<2.5) further supports the presence of a gastrinoma.
• Glucagonomas: Patients typically present with markedly elevated fasting glucagon levels, exceeding 500 pg/mL (normal range: <150 pg/mL).
• VIPomas: Excessive secretion of VIP occurs, leading to profuse watery diarrhea, hypokalemia, and achlorhydria. A fasting VIP level above 75 pg/mL (normal <50 pg/mL) is highly suggestive of this diagnosis.
• Somatostatinomas: Fasting somatostatin levels are elevated greater than 160 pg/mL (normal <100 pg/mL).

Imaging Studies

Imaging plays a crucial role in evaluating pNETs, aiding in tumor localization, staging, treatment planning, and follow-up. A multimodal imaging approach is often necessary, as different modalities offer complementary strengths depending on the tumor's size, location, grade, and functionality.

Contrast-enhanced computed tomography

Contrast-enhanced computed tomography (CT) is typically the initial diagnostic imaging modality for suspected pNETs, partly due to its widespread availability and rapid image acquisition. These tumors are generally hypervascular and best visualized during the arterial phase of a multiphasic CT scan. CT is particularly effective for assessing the primary tumor, detecting vascular involvement, and identifying metastases in the liver or lymph nodes. However, CT may miss smaller lesions or those that are isoattenuating with surrounding pancreatic tissue, and CT is generally less sensitive than magnetic resonance imaging for the identification of liver metastases.[18][19][20][21]

Magnetic resonance imaging

Magnetic resonance imaging (MRI) offers superior soft tissue contrast compared to CT and is especially valuable for detecting small lesions and evaluating hepatic metastases. The addition of dynamic contrast enhancement and diffusion-weighted imaging (DWI) enhances its sensitivity for neuroendocrine lesions. MRI demonstrates a sensitivity of approximately 8595% for liver metastases. It is preferred in patients with contrast allergies or impaired renal function and can provide more detailed tissue characterization in equivocal cases.[21]

Endoscopic ultrasound

Endoscopic ultrasound (EUS), often combined with fine-needle aspiration (FNA), offers the highest sensitivity for detecting small, subcentimeter pNETs, particularly in the pancreatic head and uncinate process. EUS is highly operator-dependent but offers the added benefit of obtaining cytological or histological samples to confirm the diagnosis and assess tumor grade. The sensitivity of EUS for detecting tumors smaller than 2 cm ranges from 79% to 100%, making it especially useful in cases where cross-sectional imaging is inconclusive.[21][22]

⁶⁸Ga-DOTATATE imaging

⁶⁸Ga-DOTATATE PET/CT has emerged as the gold standard in the functional imaging of well-differentiated pNETs. This modality targets somatostatin receptor subtype 2, which is overexpressed in most well-differentiated neuroendocrine tumors. It allows for whole-body imaging and is particularly effective in detecting small primary tumors, lymphatic spread, and distant metastases. The sensitivity of Ga-68 DOTATATE PET/CT is approximately 90% to 95%, with specificity ranging from 88% to 95%. Please refer to StatPearls' companion resource, "Octreotide Scan," for additional information.[23][24]

¹⁸F-fluorodeoxyglucose imaging

In contrast, ¹⁸F-fluorodeoxyglucose (FDG) PET/CT is typically reserved for high-grade (G3) or poorly differentiated pNETs that exhibit high metabolic activity but may not express somatostatin receptors. FDG-PET is useful for prognostication and for detecting aggressive or rapidly progressing disease. While its sensitivity is limited (approximately 50% to 70%) in well-differentiated pNETs, FDG-PET is significantly higher for poorly differentiated or high-grade tumors.[21][23][24][25][26]

Each imaging modality offers distinct advantages, and the choice of technique should be tailored to the tumor's characteristics, clinical presentation, and therapeutic goals. A combination of cross-sectional and functional imaging is often necessary for accurate staging and optimal management planning.

Treatment / Management

The management of pNETs depends on the tumor’s functionality, location within the pancreas, grade, and stage at the time of diagnosis. Surgical resection remains the cornerstone of treatment for patients with localized disease, and is also considered in select cases of metastatic disease amenable to cytoreductive surgery. For patients who are not surgical candidates or have advanced or progressive disease, treatment options include somatostatin analogs, targeted therapies such as mTOR inhibitors, peptide receptor radionuclide therapy (PRRT), and systemic chemotherapy, all of which are tailored to the tumor biology and receptor status.

Differential Diagnosis

A pNET can present with symptoms similar to those of other pancreatic and peri-pancreatic conditions, necessitating a careful differential diagnosis. Notably, pancreatic adenocarcinoma is a primary consideration. While both pNETs and pancreatic adenocarcinoma can manifest as pancreatic masses, pancreatic adenocarcinoma typically exhibits more aggressive behavior and a poorer prognosis.

Additionally, solid pseudopapillary tumors of the pancreas, which predominantly affect younger women, may mimic pNETs radiologically but often have distinct pathological features. Other conditions that can resemble pNETs include pancreatic lymphangiomas, intraductal papillary mucinous neoplasms (IPMNs), and metastatic lesions to the pancreas. Accurate differentiation among these diseases is crucial for appropriate management and relies on a combination of imaging studies, histopathological evaluation, and immunohistochemical staining.[27][28][29]

Surgical Oncology

Surgical intervention represents a cornerstone in the management of pancreatic neuroendocrine tumors (pNETs), including both functional and nonfunctional subtypes, as well as select cases of metastatic disease. The surgical approach is individualized based on tumor functionality, size, location, histologic grade, and the extent of metastatic involvement.

Functional Pancreatic Neuroendocrine Tumors

Surgical resection is the primary modality of treatment for functional pNETs, offering both definitive control of hormone-mediated symptoms and potential for cure. The choice of surgical technique is guided by tumor size and its anatomical relationship to the main pancreatic duct. Small (<2 cm), well-circumscribed, and well-differentiated tumors located away from the ductal system may be amenable to enucleation, which preserves pancreatic parenchyma and minimizes the risk of postoperative endocrine or exocrine insufficiency.

Conversely, larger lesions or those situated adjacent to the main pancreatic duct generally necessitate formal pancreatectomy. This may include a distal pancreatectomy for tumors in the body or tail, a pancreaticoduodenectomy (Whipple procedure) for lesions in the pancreatic head, or a central pancreatectomy for mid-gland tumors. Regional lymphadenectomy is routinely performed for oncologic staging and may confer prognostic benefit. Surgical resection of functional pNETs, when technically feasible, is associated with favorable outcomes, particularly in patients with low-grade, well-differentiated neoplasms.[30][31]

Nonfunctional Pancreatic Neuroendocrine Tumors

The management of nonfunctional pNETs is predicated upon tumor size, proliferative index, and radiographic behavior over time. Small (≤2 cm), asymptomatic, and well-differentiated tumors can be observed with active surveillance, particularly in older patients or those with significant comorbidities. However, lesions exceeding 2 cm, demonstrating interval growth, irregular imaging characteristics, or elevated Ki-67 indices are typically managed with surgical resection. Enucleation may still be appropriate for select tumors that are safely distanced from the pancreatic duct.

Still, formal resection—eg, distal pancreatectomy, pancreaticoduodenectomy, or central pancreatectomy—is often warranted for definitive treatment. The surgical strategy is dictated by the tumor's anatomic location and proximity to critical vasculature or ductal structures. Regional lymphadenectomy is generally indicated in cases with higher malignant potential. Surgical resection remains the most effective intervention for long-term disease control and is particularly important in patients at elevated risk for recurrence or metastasis.[30][32][31]

Cytoreductive Surgery in Metastatic Pancreatic Neuroendocrine Tumors

In patients with metastatic disease, particularly with hepatic involvement, cytoreductive surgery may confer symptomatic and survival benefits in appropriately selected individuals. Debulking procedures that achieve resection of 70% or more of the tumor burden have demonstrated improvements in overall survival and symptom palliation in both functional and nonfunctional metastatic pNETs. Optimal candidates for cytoreduction typically have well-differentiated tumors, limited extrahepatic spread, and preserved hepatic function. Surgical techniques include formal hepatic resection, enucleation of dominant liver metastases, and adjunctive modalities such as radiofrequency or microwave ablation. Notably, even in cases where hepatic metastases are unresectable, resection of the primary pancreatic lesion can improve outcomes by reducing the risk of future complications and possibly confer a survival benefit. This approach is currently under active investigation.[33][34][35]

Prophylactic Cholecystectomy

Although not routinely mandated, prophylactic cholecystectomy should be considered in patients anticipated to undergo prolonged therapy with somatostatin analogs. Long-term use of these agents is associated with an increased risk of cholelithiasis and cholecystitis. Performing a cholecystectomy at the time of initial pancreatic surgery may mitigate future biliary complications and reduce the need for reoperation.

Radiation Oncology

Radiation therapy plays an adjunctive role in the interprofessional management of pNETs. Although pNETs have historically been regarded as relatively radioresistant, emerging evidence supports the utility of radiotherapeutic modalities in select clinical scenarios, primarily for symptom palliation and locoregional disease control in patients with unresectable or progressive tumors.

External Beam Radiotherapy 

Conventional external beam radiotherapy (EBRT) is not typically considered a primary treatment modality for pNETs. Still, it has demonstrated efficacy in achieving local tumor control and symptomatic relief, particularly in patients with unresectable, recurrent, or locally advanced disease. EBRT may induce radiographic tumor response or disease stabilization in a substantial subset of patients. It may be employed for palliation in the setting of bulky hepatic disease or metastatic lesions involving retroperitoneal structures, where tumor growth could compromise adjacent organ function, leading to obstructive symptoms, hemorrhage, or refractory pain. Additionally, EBRT is effective in palliating painful osseous metastases by achieving stabilization and decreasing skeletal-related events.[36][37]

Stereotactic Body Radiotherapy 

Stereotactic body radiotherapy (SBRT) has emerged as a promising treatment option for select patients with small, well-differentiated pNETs or oligometastatic disease. SBRT delivers high-dose, conformal radiation to the target lesion with sub-millimeter accuracy, thereby sparing surrounding normal tissues. This technique has demonstrated favorable local control rates and acceptable toxicity profiles, particularly for hepatic or pulmonary metastases. While prospective, randomized data are limited, retrospective analyses support SBRT as a feasible and well-tolerated intervention in patients with localized or oligoprogressive disease.[37][38]

Peptide Receptor Radionuclide Therapy 

Peptide receptor radionuclide therapy (PRRT) has become a validated systemic treatment strategy for patients with advanced, unresectable, or metastatic well-differentiated pNETs that express somatostatin receptors. PRRT utilizes radiolabeled somatostatin analogs, such as ^177Lu-DOTATATE, to deliver targeted internal radiation, resulting in tumor cytotoxicity and clinical benefit. This modality is most effective in tumors with a Ki-67 index of ≤20% and strong somatostatin receptor expression, as confirmed by Ga-68 DOTATATE PET/CT. PRRT is associated with high disease control rates, meaningful symptomatic improvement, and a generally favorable toxicity profile, making it a key component of treatment for receptor-positive pNETs.[37][39][40]

Selective Internal Radiation Therapy 

Selective internal radiation therapy (SIRT), also known as radioembolization, involves the transarterial delivery of ⁹⁰Yttrium-labeled microspheres to hepatic metastases via the hepatic artery. This locoregional treatment is beneficial in patients with liver-dominant metastatic disease and offers targeted tumor irradiation while minimizing off-target toxicity. Although high-level prospective data are lacking, retrospective series and case reports have demonstrated significant tumor shrinkage, disease stabilization, and symptomatic benefit in carefully selected patients. SIRT may be considered in patients with unresectable liver metastases who are not candidates for resection or ablation.[37][39]

Conclusion

Radiation-based therapies are an essential component of the therapeutic armamentarium for pNETs when used judiciously and individually. Selection of the appropriate radiotherapy modality should be based on the tumor's histology, the anatomical distribution of the disease, functional imaging findings, and the patient's performance status. Integration of radiation therapy into a broader interprofessional treatment plan is essential for optimizing outcomes in this heterogeneous disease.

Medical Oncology

Medical management is indicated in unresectable, advanced, recurrent, or metastatic pNETs. Key therapeutic modalities encompass a range of systemic therapies tailored to tumor grade, differentiation, and disease progression. These include somatostatin analogs, mTOR inhibitors, peptide receptor radionuclide therapy, and chemotherapy.

Somatostatin Analogs

According to NCCN and ENETs guidelines, long-acting somatostatin analogs, eg, octreotide long-acting release (LAR) and lanreotide, are foundational in the treatment of well-differentiated, unresectable, or metastatic pNETs with a low proliferation index and positive expression of somatostatin receptor. These agents bind to somatostatin receptors on tumor cells, inhibiting hormone secretion and exerting antiproliferative effects.

Clinical studies — most notably the PROMID study in patients with midgut NETs and the CLARINET study in a broader cohort of gastroenteropancreatic NETs— have demonstrated their efficacy in symptom control and tumor stabilization, particularly in tumors with a Ki-67 index <10% and limited hepatic tumor burden. However, their antiproliferative activity may be less pronounced in higher-grade tumors or those with extensive liver involvement. Adverse effects include gastrointestinal disturbances (eg, steatorrhea and abdominal bloating), biliary lithiasis resulting from reduced gallbladder contractility, and occasional dysglycemia.[18][37]

Targeted Therapies With mTOR Inhibitors

The mammalian target of rapamycin (mTOR) pathway is integral to cell growth and proliferation in pNETs. Everolimus, an oral mTOR inhibitor, has been approved for the treatment of advanced pNETs, demonstrating a significant improvement in progression-free survival in the RADIANT-3 clinical trial. Despite its benefits, resistance to mTOR inhibition can develop, necessitating ongoing research into combination therapies and alternative pathways to overcome therapeutic resistance. Common adverse effects include stomatitis, hyperglycemia, dyslipidemia, fatigue, and immunosuppression, all of which necessitate vigilant metabolic and hematologic monitoring.[37][41]

Peptide Receptor Radionuclide Therapy 

PRRT with ¹⁷⁷Lu-DOTATATE offers targeted radiotherapy for patients with somatostatin receptor-positive, well-differentiated pNETs. This therapy delivers radiation directly to tumor cells, leading to tumor regression and symptom relief. Please see StatPearls' companion resource, "Neuroendocrine Tumor Lu ¹⁷⁷Dotate Therapy," for further information on ¹⁷⁷Lu-dotatate therapy.[42] The NETTER-1 trial demonstrated a significant improvement in progression-free survival and quality of life with 177Lu-dotatate compared to high-dose octreotide LAR in patients with metastatic midgut NETs. The NETTER-2 trial established extended progression-free survival with ¹⁷⁷Lu-dotatate and high-dose octreotide LAR in patients with grade 2 or 3 advanced gastroenteropancreatic NETs, supporting its potential as first-line therapy for more aggressive NETs. While generally well-tolerated, potential hematologic and renal toxicities necessitate careful patient selection and monitoring.[37][43][44]

Chemotherapy

Chemotherapy is typically reserved for high-grade, poorly differentiated, or rapidly progressing pNETs. Platinum-based regimens, such as cisplatin or carboplatin combined with etoposide, are the standard first-line therapy. Alkylating agents, such as temozolomide, often combined with capecitabine (CAPTEM regimen), have demonstrated efficacy in inducing tumor responses. This combination is particularly beneficial for patients with intermediate to high Ki-67 indices. However, chemotherapy's role is limited in well-differentiated, low-grade tumors due to modest response rates and potential toxicity. Specifically, platinum agents can cause nephrotoxicity and ototoxicity, while temozolomide is associated with myelosuppression and gastrointestinal disturbances.[37][45]

Staging

The following staging of pNETs is based on the TNM system, as outlined by the American Joint Committee on Cancer (AJCC) 8th Edition and the European Neuroendocrine Tumor Society (ENETS):

• Primary Tumor (T)
  • T1: Tumor ≤2 cm, limited to the pancreas
  • T2: Tumor >2 cm but ≤4 cm, limited to the pancreas
  • T3: Tumor >4 cm or invading the duodenum or the common bile duct
  • T4: Tumor involves adjacent organs or major vessels (eg, celiac axis, SMA)
• Regional Lymph Nodes (N)
  • N0: No regional lymph node metastasis
  • N1: Regional lymph node metastasis present
• Distant Metastasis (M)
  • M0: No distant metastasis
  • M1: Distant metastasis (eg, liver, lung, bone)

Tumor grade, based on the Ki-67 index and mitotic rate, is also a crucial prognostic factor and is classified separately as G1 (low), G2 (intermediate), or G3 (high). Please see the histopathology of pNETs. 

Prognosis

The prognosis of pNETs is influenced by multiple factors, including tumor grade, stage, differentiation, functionality, and treatment approach. One of the most significant prognostic indicators is tumor grade, which is determined by the mitotic count and Ki-67 proliferation index. Well-differentiated, low-grade tumors (G1, Ki-67 ≤2%) are associated with excellent outcomes, with 5-year survival rates approaching 90%. High-grade (G3, Ki-67 >20%) or poorly differentiated tumors behave aggressively and carry a much poorer prognosis, with 5-year survival often below 40%.[7][46]

The stage at diagnosis also plays a crucial role. Patients with localized or resectable disease have better outcomes compared to those with advanced or metastatic disease. Individuals who undergo complete (R0) surgical resection can achieve 5-year survival rates ranging from 65% to 100%, depending on the tumor biology and functionality. Conversely, patients with liver metastases typically have a median survival of approximately 2 to 4 years.

Functionality is another important determinant of prognosis as functional pNETs often present earlier due to hormone-related symptoms, which can lead to earlier diagnosis and intervention. As a result, functional pNETs tend to have a more favorable prognosis than nonfunctional tumors, which frequently remain asymptomatic until they are large or metastatic. Surgical management remains the cornerstone of curative treatment, significantly improving long-term outcomes. Even in patients with limited hepatic metastasis, surgical debulking or resection of the primary tumor may confer survival benefits and symptom control.[46][47]

Complications

The treatment of pNETs can lead to several complications depending on the modality used. Surgical resection, while potentially curative, carries risks that are inherent to pancreatic surgery, eg, pancreatic fistulas, infections, or new-onset diabetes. Medical therapies like somatostatin analogs can cause gastrointestinal disturbances and gallstones, while targeted agents such as everolimus and sunitinib are associated with stomatitis, hyperglycemia, hypertension, and immunosuppression. Peptide receptor radionuclide therapy may result in myelosuppression and renal toxicity, and liver-directed treatments can cause post-embolization syndrome or hepatic insufficiency. Close monitoring and interprofessional management are crucial for mitigating these risks and enhancing patient outcomes.