What Is Neuroendocrine Pancreatic Cancer?

Neuroendocrine pancreatic cancer is a relatively uncommon malignancy that arises from hormone-producing cells scattered throughout the pancreas. These tumors, formally called pancreatic neuroendocrine tumors (PanNETs), account for a small fraction of all pancreatic cancers but behave very differently from the far more common pancreatic adenocarcinoma. Most grow slowly, many are discovered by accident on imaging done for unrelated reasons, and survival rates are substantially better. That said, the disease spans a wide spectrum, from tiny, indolent tumors that can be safely watched to aggressive, rapidly growing cancers that require urgent treatment.

What Makes These Tumors Different From “Regular” Pancreatic Cancer

When most people hear “pancreatic cancer,” they think of pancreatic ductal adenocarcinoma, the disease with notoriously poor outcomes. Neuroendocrine tumors of the pancreas originate from an entirely different cell population. The pancreas contains clusters of endocrine cells (the islets of Langerhans) that produce hormones like insulin, glucagon, and gastrin. When these cells become cancerous, the resulting tumor retains some of that hormone-producing machinery and expresses shared markers such as synaptophysin and chromogranin A.¹ This biological origin explains both the unusual symptoms these tumors can cause and the specialized treatments available for them.

Grading and Why It Matters So Much

The single most important factor driving treatment decisions is the tumor’s grade, which reflects how quickly the cancer cells are dividing. Pathologists determine this by measuring the Ki-67 index, a marker of cell proliferation that has become an essential part of classifying these tumors.² The World Health Organization system divides pancreatic neuroendocrine neoplasms into three grades. Grade 1 (G1) and Grade 2 (G2) tumors are well-differentiated, meaning the cells still resemble normal neuroendocrine cells under the microscope and tend to grow more slowly. Grade 3 (G3) neoplasms include both well-differentiated tumors with a high proliferation rate and poorly differentiated neuroendocrine carcinomas, which are aggressive and behave more like other high-grade cancers.³

This grading system is not just an academic exercise. A G1 tumor may sit quietly for years and never spread, while a poorly differentiated G3 neuroendocrine carcinoma can metastasize widely and carry a prognosis closer to that of adenocarcinoma. Different Ki-67 counting methods, whether manual, digital, or by eyeball estimation, show strong agreement with each other and all correlate with patient survival.⁴

Functioning Versus Nonfunctioning Tumors

One of the unusual features of pancreatic neuroendocrine tumors is that some actively secrete hormones in quantities large enough to cause distinct clinical syndromes. These are called “functioning” tumors. Others, called “nonfunctioning,” may still release substances like chromogranin A or pancreatic polypeptide into the blood, but not at levels that produce recognizable symptoms.⁵ Nonfunctioning tumors are more common and are often found later, either because they grow large enough to press on surrounding structures or because they show up incidentally during imaging for something else.

The most well-known functioning subtypes include:

Insulinoma: Secretes excess insulin, causing episodes of dangerously low blood sugar. Patients may experience confusion, sweating, tremors, or even seizure-like episodes that can initially be mistaken for neurological disorders.⁶
Gastrinoma: Overproduces gastrin, leading to Zollinger-Ellison syndrome, which is characterized by severe acid reflux, recurrent peptic ulcers, and chronic diarrhea caused by massive stomach acid overproduction.⁷
Glucagonoma: Secretes glucagon and produces a distinctive skin rash called necrolytic migratory erythema, along with diabetes and weight loss. In a small case series, every patient first visited a dermatologist for the rash before the underlying tumor was identified.⁸
VIPoma: Secretes vasoactive intestinal peptide, causing profuse watery diarrhea, low potassium, and dehydration.

These hormone-driven syndromes sometimes lead to earlier detection, because the symptoms are hard to ignore. Ironically, the “silent” nonfunctioning tumors tend to be found at a more advanced stage precisely because they do not announce themselves.

Genetic Roots

Most pancreatic neuroendocrine tumors arise sporadically, without a clear inherited cause. But roughly one in ten is linked to a hereditary syndrome, including multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau disease, neurofibromatosis type 1, and tuberous sclerosis complex.⁹ People with these conditions develop tumors at younger ages and often in multiple endocrine organs simultaneously, so screening protocols are more aggressive for them.

Even in sporadic tumors, the molecular landscape is distinctive. A landmark genomic study found that the most commonly mutated genes involve chromatin remodeling. About 44% of tumors carried inactivating mutations in MEN1, and 43% had mutations in either DAXX or ATRX, two genes that work together in a chromatin-remodeling complex. Mutations in the mTOR signaling pathway were found in about 14% of cases.¹⁰ These patterns have real clinical implications: the mTOR pathway finding, for example, directly informed the development of targeted drug treatments. In smaller tumors (2 cm or under), mutations are less frequent overall, but MEN1 remains the most commonly affected gene, and DAXX mutations appear to be a marker of tumors that may behave more aggressively.¹¹

Researchers have also begun classifying these tumors into molecular subtypes based on DNA methylation patterns. One study identified three distinct subgroups. One subgroup had few mutations in the commonly affected genes and was enriched for functioning tumors. A second harbored frequent DAXX/ATRX mutations, had longer telomeres, tended to be larger, and carried most of the mTOR pathway mutations. A third was characterized by MEN1 mutations, a higher proportion of G1 tumors, and less spread beyond the pancreas, suggesting a better prognosis.¹² This kind of molecular subtyping is still largely a research tool, but it points toward a future where treatment could be tailored to a tumor’s specific biology rather than its size or grade alone.

How These Tumors Are Found and Diagnosed

Chromogranin A, a protein released by neuroendocrine cells, is the most widely used blood marker. Its usefulness has limits, though. In one prospective study, the overall sensitivity of chromogranin A for detecting a pancreatic neuroendocrine tumor was only about 49%, with the test performing better for larger tumors, where sensitivity rose to around 64%.¹³ Common medications like proton pump inhibitors (widely prescribed for acid reflux) can falsely elevate chromogranin A levels, further muddying the picture. When patients on these drugs were excluded from one analysis, diagnostic accuracy dropped.¹⁴ So a normal chromogranin A level does not rule out a tumor, and an elevated one does not confirm it.

Imaging plays the more decisive role. A specialized PET scan using gallium-68 DOTATATE, a radioactive tracer that binds to somatostatin receptors on the surface of most neuroendocrine tumor cells, is highly effective at finding well-differentiated tumors. Detection rates reached 95% for G1 tumors in one study, though they dropped to about 38% for G3 tumors, which tend to lose those surface receptors. Combining DOTATATE PET with FDG PET (which lights up metabolically active, fast-growing cells) or with MRI raised the detection rate to 100% across all grades.¹⁵ DOTATATE PET also picked up small metastatic lymph node and bone lesions that were missed by other tracers in a head-to-head comparison.¹⁶ This dual-tracer approach gives clinicians a remarkably detailed picture of both slow-growing and aggressive disease.

Surgery and the Growing Role of Observation

Surgery remains the only cure for localized pancreatic neuroendocrine tumors, but not every tumor needs to come out. For small, nonfunctioning tumors, a significant shift toward watch-and-wait has taken place. Data from the National Cancer Database show that observation of small tumors (2 cm or under) roughly tripled over a decade, rising from about 16% in 2010 to nearly 45% in 2020. Among the smallest tumors (1 cm or under), observation rose from about 19% to 52%.¹⁷ An earlier analysis of over a decade of national data concluded that active surveillance appears safe for nonfunctioning tumors under 1 cm, while larger tumors likely still benefit from surgical intervention.¹⁸

When surgery is needed, the approach depends on the tumor’s size and location. Enucleation, essentially shelling the tumor out of the pancreas without removing a large section of the organ, preserves more pancreatic tissue and significantly reduces the risk of long-term endocrine and exocrine insufficiency compared with standard resections like the Whipple procedure or distal pancreatectomy. A meta-analysis found the risk of developing diabetes or digestive enzyme deficiency after enucleation was a fraction of the risk after formal resection. The trade-off is a higher rate of postoperative pancreatic fistula, a leak of pancreatic fluid that usually resolves with conservative management.¹⁹ Long-term recurrence-free survival and overall mortality were comparable between the two approaches.²⁰

Drug Treatments for Advanced Disease

When a pancreatic neuroendocrine tumor has spread beyond what surgery can address, several drug classes can slow its growth. Somatostatin analogs, synthetic versions of a natural hormone that puts the brakes on hormone secretion and cell growth, are often the first-line systemic treatment. The CLARINET trial demonstrated that lanreotide more than doubled the proportion of patients alive without disease progression at two years compared with placebo, with a hazard ratio of 0.47 for progression or death.²¹ Octreotide, the other widely used somatostatin analog, has shown similar antiproliferative benefit, initially established in midgut neuroendocrine tumors and extended into broader use.²² A long-term retrospective study found no meaningful difference in progression-free survival between lanreotide and octreotide, with median values around 30 and 36 months respectively, and overall survival exceeding seven years for both.²³

When disease progresses on somatostatin analogs, targeted therapies enter the picture. Everolimus, an mTOR inhibitor, more than doubled median progression-free survival compared with placebo in a pivotal trial (about 11 months versus roughly 5 months), representing a 65% reduction in the risk of disease progression or death.²⁴ Sunitinib, a drug that targets the blood vessel growth tumors depend on, is the other approved targeted agent for advanced disease.²⁵ The approval of both drugs was directly informed by the molecular findings showing that mTOR pathway and angiogenesis genes are commonly altered in these tumors.²⁶

Peptide Receptor Radionuclide Therapy

One of the most significant treatment advances for neuroendocrine tumors is peptide receptor radionuclide therapy, or PRRT, which delivers targeted radiation directly to tumor cells. The treatment uses lutetium-177 attached to a molecule (DOTATATE) that binds to somatostatin receptors on the tumor surface, essentially turning the tumor’s own biology into a homing beacon for radiation. In patients with advanced pancreatic neuroendocrine tumors who had already been heavily treated with chemotherapy, lutetium-177 DOTATATE achieved a median progression-free survival of 24 months and a median overall survival of 42 months.²⁷

A meta-analysis comparing PRRT head-to-head with everolimus found that lutetium-177 DOTATATE had a higher response rate (47% versus 12%), longer progression-free survival (about 26 months versus 15 months), and fewer side effects that led to treatment discontinuation. In the everolimus group, 59 out of 371 patients stopped treatment due to adverse events. In the PRRT group, none of 128 patients did.²⁸ PRRT does carry a risk of bone marrow suppression and, rarely, secondary leukemia, but its combination of efficacy and tolerability has made it a cornerstone of treatment for somatostatin receptor-positive disease. Researchers have also shown that tumor growth rates reverse dramatically after starting PRRT: tumors that were growing at an average rate of about 6% per month before treatment began shrinking at roughly 3% per month within a few months of starting therapy.²⁹

Liver-Directed Treatments

The liver is the most common site of metastasis for pancreatic neuroendocrine tumors, and for patients with liver-dominant disease, locally targeted treatments can play a major role. Techniques like transarterial embolization and transarterial chemoembolization work by cutting off the blood supply to liver tumors, which can quickly shrink tumor bulk and relieve hormone-related symptoms. These approaches have demonstrated effectiveness in reducing tumor volume, improving symptoms, and delaying further disease progression. A practical consideration is that patients whose tumors still express somatostatin receptors and who may later be candidates for PRRT might benefit from embolization-based approaches first, preserving the PRRT option for later use.³⁰

Immunotherapy and Its Uncertain Role

Immune checkpoint inhibitors have transformed treatment for many cancers, but their role in pancreatic neuroendocrine tumors remains unclear. Most well-differentiated pancreatic neuroendocrine tumors have low expression of PD-1 and PD-L1, the immune checkpoint targets that drugs like pembrolizumab block. Poorly differentiated neuroendocrine carcinomas show somewhat higher levels of these markers and more immune cell infiltration, suggesting they may be more amenable to immunotherapy.³¹

Clinical trial results have been modest so far. The KEYNOTE-158 trial, which included 107 patients with neuroendocrine tumors, found an overall response rate of just under 4% with pembrolizumab, including three partial responses in patients with pancreatic tumors.³² A more encouraging signal has emerged in a niche setting: patients whose tumors developed a high mutation burden and mismatch repair deficiency after prior treatment with alkylating chemotherapy. In that group, immunotherapy produced a response rate of 44% and a median progression-free survival of nearly 9 months when mismatch repair deficiency was present, compared with 7% and under 3 months without it.³³ This suggests immunotherapy could eventually play a role, but only in carefully selected patients whose tumors have specific molecular characteristics.

Living With the Disease

Because many patients with pancreatic neuroendocrine tumors live for years or even decades with their disease, quality of life is a central concern, not a secondary one. Even among patients receiving PRRT, quality-of-life assessments reveal meaningful impairments in fatigue, appetite, diarrhea, and physical and social functioning compared with the general population.³⁴ Hormone-related symptoms in patients with functioning tumors can be profoundly disruptive. Uncontrolled diarrhea, blood sugar crashes, or severe skin rashes affect daily life in ways that pure survival statistics do not capture.

Patients who undergo pancreatic surgery face their own long-term challenges. Depending on how much of the pancreas is removed, some develop diabetes or lose the ability to produce adequate digestive enzymes, requiring lifelong insulin or enzyme replacement. The shift toward enucleation for small tumors and observation for the smallest ones reflects an awareness that the treatment itself carries consequences. For patients on somatostatin analogs, the injections are typically given monthly and are generally well tolerated, but they are a long-term commitment rather than a short course of treatment. The broader point is that managing this disease is rarely about a single dramatic intervention; it is about balancing tumor control with everyday functioning over what can be a very long disease course.

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