Somatostatinoma

Etiology

Somatostatinoma can occur sporadically or in association with genetic syndromes characterized by mutations in key genes involved in tumor growth, often presenting with a range of clinical features. These syndromes include multiple neuroendocrine type 1 (MEN1), von Hippel-Lindau (VHL) syndrome, tuberous sclerosis, and neurofibromatosis type 1 (NF1). Polycythemia-paraganglioma-somatostatinoma syndrome (also known as Pacak-Zhuang syndrome) is a recently described syndrome that has been associated with somatostatinoma (see Table 1. Somatostatinoma Associated Syndromes).[8][9][10][11][12]

Table 1. Somatostatinoma Associated Syndromes

Epidemiology

The median age of presentation of somatostatinoma is 50, with a noted female predominance.[13] Some estimates suggest an annual incidence of 1 in 40 million individuals.[7] An analysis of the Surveillance, Epidemiology, and End Results (SEER) database in the United States demonstrated a 6.4-fold increase in the annual incidence of NETs, with somatostatinoma accounting for only 4% of the pancreatic NETs.[1][2] 

Somatostatinomas are typically solitary tumors, with approximately half arising in the pancreas, of which 50% are located in the pancreatic head. At the same time, the remainder occurs in the duodenum or other parts of the small intestine.[14] Somatostatinomas have also been reported in a few extraintestinal sites, eg, the kidneys, lungs, and thyroid. 

Pathophysiology

Previously, a clear consensus defining the functional nature of NETs was lacking. This was addressed in the 2023 European Neuroendocrine Tumor Society (ENETS) guidance paper.[15][16] A NET is considered a somatostatinoma only if associated with a clinical syndrome and evidence of inappropriate somatostatin levels. NETs that produce hormone variants or insufficient amounts of the hormone are not considered functional. The current WHO classification further clarifies that a NET with positive immunohistochemistry for somatostatin without symptoms would be classified as somatostatin-producing well-differentiated NET.

The clinical syndrome associated with somatostatinoma results from the excessive production of somatostatin. This classic triad includes diabetes mellitus, steatorrhea, and cholelithiasis. Somatostatin reduces gastrointestinal motility, gallbladder contraction, and inhibits the secretion of multiple hormones, including growth hormone, insulin, glucagon, TSH, secretin, and cholecystokinin. Somatostatin also has a direct inhibitory effect on gastric acid secretion, splanchnic perfusion, and gastric emptying.[17] In some cases, somatostatinomas may present with jaundice or gastrointestinal bleeding. 

Histopathology

Somatostatinomas are typically well-differentiated and exhibit a glandular pattern with cells rich in neurosecretory granules. In contrast, poorly differentiated somatostatinomas display less resemblance to nonneoplastic cells and are characterized by a sheet-like or diffuse architectural pattern, irregular nuclei, and reduced cytoplasmic granularity. Biopsy of the NET is essential to confirm the diagnosis and determine the tumor grade, which is critical for treatment planning.

According to the 2022 WHO classification of NETs, somatostatinomas are categorized as either well-differentiated NETs or poorly differentiated NECs (see Table 2. 2022 WHO Classification of Neuroendocrine Tumors).[15] However, NECs are less likely to produce any hormone-related symptoms.[18] Well-differentiated NETs are further graded based on the Ki-67 expression and mitotic count.[19]

Table 2. 2022 WHO Classification of Neuroendocrine Tumors

Immunohistochemical staining is used to detect somatostatin, as well as other markers, eg, cytokeratins, insulinoma-associated protein 1 (INSM1), synaptophysin, and chromogranin A. Psammoma bodies are concentric lamellated calcified structures commonly visualized in duodenal tumors more than in pancreatic tumors.[20] In approximately one-fourth of the cases, the tumor also stains positive for other pancreatic hormones, including insulin, calcitonin, gastrin, glucagon, and vasoactive intestinal polypeptide.[7]

History and Physical

Somatostatinoma Clinical Features

The classic symptoms associated with excess somatostatin production include diabetes mellitus, cholelithiasis, and steatorrhea, which result from the hormone's inhibitory effects on insulin secretion, cholecystokinin release, and pancreatic exocrine enzyme activity. These disruptions lead to impaired glucose regulation, bile stasis, and fat malabsorption, respectively. Additional clinical features may include achlorhydria due to suppressed gastric acid secretion, unintentional weight loss, and central hypothyroidism from reduced TSH levels. Depending on the tumor's anatomical location, particularly in the periampullary or pancreatic regions, patients may also present with obstructive jaundice, abdominal pain, pruritus, or even acute pancreatitis due to biliary or pancreatic duct obstruction.[8]

As the disease progresses, approximately 3% to 6% of patients may develop other functional syndromes, reflecting broader neuroendocrine involvement.[16] Importantly, somatostatinomas can occur sporadically or in association with hereditary endocrine syndromes, eg, MEN1, NF1, and VHL syndrome. Therefore, clinicians should maintain a high index of suspicion and carefully evaluate for signs and symptoms suggestive of an underlying genetic disorder, particularly in patients with a personal or family history of endocrine tumors or multiple synchronous neoplasms.

Evaluation

The diagnosis of somatostatinoma requires a comprehensive, stepwise approach that integrates clinical assessment, biochemical testing, and advanced imaging to confirm functionality, localize the tumor, and assess for metastatic disease.

Biochemical Testing

Although a definitive threshold for fasting plasma somatostatin levels has not been universally established, ENETS recommends a diagnostic cutoff exceeding 2 to 3 times the upper reference limit (ie, >60 pg/mL when the upper limit is >30 pg/mL).[16] Additional non-specific markers, eg, chromogranin A and pancreatic polypeptide, are often elevated in pancreaticoduodenal NETs. While chromogranin A helps track treatment response and disease recurrence, its clinical utility is limited by a high false-positive rate in the context of physiological stress, hepatic or renal impairment, and proton pump inhibitor use.

Imaging Studies

Accurate imaging is essential for evaluating the extent of disease and determining resectability. A combination of the following modalities is typically employed:

• Cross-sectional imaging: On noncontrast CT, somatostatinomas typically appear isodense relative to pancreatic parenchyma. They demonstrate homogeneous arterial phase enhancement with contrast enhancement, often becoming less conspicuous during the portal venous phase (see Image. Somatostatinoma).[21] MRI offers superior sensitivity for detecting hepatic and osseous metastases and is usually complementary to CT.
• Endoscopic ultrasound(EUS): EUS is highly sensitive and specific for detecting pancreatic neuroendocrine neoplasms, including lesions smaller than 5 mm. It is particularly advantageous for identifying small or submucosal somatostatinomas that may not be visualized on conventional cross-sectional imaging.[22]
• Functional imaging (PET): Somatostatin receptor-based positron emission tomography (PET) using radiolabeled ligands such as ⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTATOC,⁶⁸Ga-DOTANOC, or ⁶⁴Cu-DOTATATE demonstrates excellent sensitivity and specificity for tumor localization and staging. High radiotracer uptake also serves as a predictive biomarker for responsiveness to PRRT.

Histopathological Confirmation

Tissue sampling is essential for establishing a definitive diagnosis and determining tumor grade. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and fine needle biopsy (EUS-FNB) are preferred methods for obtaining cytological or histological specimens. When EUS is not feasible, image-guided percutaneous biopsies may be employed using CT, MRI, or ultrasound.

Treatment / Management

The management of somatostatinoma requires an interprofessional, individualized approach tailored to tumor grade, anatomical site, disease extent, and patient-specific factors, including comorbidities and surgical candidacy. Treatment strategies encompass surgical resection, liver-directed therapies, somatostatin analogues, PRRT, targeted agents, and chemotherapy.

Localized Disease

Surgical resection remains the cornerstone of therapy in patients with localized or potentially resectable disease. Curative resection should be pursued whenever feasible, barring significant surgical risk or limited life expectancy. Small, well-demarcated tumors may be amenable to enucleation, particularly when situated away from major ducts and vessels. Intraoperative ultrasound can facilitate the identification of occult or small lesions, improving surgical outcomes.

For tumors unsuitable for enucleation, anatomic resections, eg, pylorus-preserving pancreaticoduodenectomy, distal pancreatectomy, or central pancreatectomy, are selected based on tumor location. Although data specific to somatostatinoma are limited due to its rarity, surgical resection of the primary tumor has been associated with symptom relief and prolonged survival in functional pancreatic neuroendocrine tumors (pNETs).

Hepatic Metastases

The liver is the most common site of metastasis in somatostatinoma. In appropriately selected patients with limited hepatic involvement, combined resection of the primary tumor and liver metastases may result in improved progression-free survival.[23] Other liver-directed options include radiofrequency ablation (RFA), microwave ablation, transarterial embolization (TAE), transarterial chemoembolization (TACE), irreversible electroporation, and brachytherapy. These modalities may be considered for cytoreduction or palliation, particularly in patients who are not candidates for hepatic resection.(B3)

Advanced and Metastatic Disease

For patients with unresectable or metastatic (stage IV) disease, treatment goals shift toward symptom control and disease stabilization. International guidelines, including those from ENETS, NANETS, ESMO, and ASCO, recommend a tiered therapeutic strategy based on tumor grade, somatostatin receptor expression, and tumor progression.[16][24][25][26] This step-wise approach includes:(A1)

• Somatostatin analogues: Long-acting somatostatin analogues such as octreotide and lanreotide are the first-line medical therapy for well-differentiated (G1/G2) tumors with low tumor burden and indolent behavior. These agents help alleviate hormone-mediated symptoms and have demonstrated antiproliferative effects. Common adverse effects include gastrointestinal disturbances, gallstone formation, and alterations in glucose metabolism. Over time, patients may experience symptomatic breakthroughs, necessitating dose adjustments or temporary drug holidays.
• Peptide receptor radionuclide therapy (PRRT): For somatostatin receptor–positive tumors, PRRT with ¹⁷⁷Lu-DOTATATE provides a targeted systemic approach with demonstrated progression-free and overall survival improvement. Candidates for PRRT should undergo somatostatin receptor imaging to confirm adequate radiotracer uptake, which predicts treatment responsiveness.
• Targeted therapies: In tumors lacking somatostatin receptor expression or those with progressive disease, molecular targeted therapies such as everolimus (an mTOR inhibitor) and sunitinib (a tyrosine kinase inhibitor) have shown clinical efficacy. These agents offer a noncytotoxic alternative for disease control, particularly in patients with intermediate-grade tumors or PRRT-refractory disease.
• Cytotoxic chemotherapy: For patients with high-grade or poorly differentiated tumors or those with rapidly progressing disease, cytotoxic chemotherapy remains a viable option. Regimens, eg, capecitabine plus temozolomide (CAPTEM) or 5-fluorouracil with streptozotocin, have shown modest response rates.[25]
• Cytoreductive surgery: In select patients with extensive but stable metastatic disease and functional symptoms, cytoreductive surgery may be considered to reduce tumor burden and hormonal output. While not curative, this approach can enhance quality of life and augment the efficacy of adjunct medical therapies.[27]
(A1)

Differential Diagnosis

Symptoms related to the biliary obstruction are differentiated from other extrahepatic causes of cholestasis, eg, choledocholithiasis, choledochal cyst, sclerosing cholangitis, cholangiocarcinoma, pancreatic pseudocysts, and pancreatic adenocarcinoma. Similarly, symptoms secondary to pancreatic insufficiencies, eg, steatorrhea and insulin-dependent diabetes, should raise suspicion of somatostatinoma in addition to chronic pancreatitis and other pancreatic tumors. 

Staging

The ninth edition of the AJCC on pancreatic NET divides staging into 4 stages (see Table. Pancreatic NET Staging).[28] 

Table 3. Pancreatic NET Staging

TNM staging is as follows:

• T stage
  • T1: Tumor limited to the pancreas, ≤2 cm in greatest dimension
  • T2: Tumor limited to the pancreas, >2 cm but ≤4 cm in greatest dimension
  • T3: Tumor limited to the pancreas, >4 cm in greatest dimension; or tumor invading the duodenum, ampulla of Vater, or common bile duct
  • T4: Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis or the superior mesenteric artery/vein, splenic artery/ vein, gastroduodenal artery/vein, portal vein)
• N stage
  • N0: No tumor involvement of regional nodes
  • N1: Tumor involvement of nodes
• M stage
  • M0: No distant metastasis
  • M1: Distant metastasis

Prognosis

The 5-year survival rate of patients with pancreatic or periampullary somatostatinoma ranges from 60% to 100% in cases of localized disease and from 15% to 60% with metastatic disease.[6] Prognosis depends on several factors, including tumor size, the degree of cytological differentiation, the amount of residual tumor after resection, and the extent of metastasis.[29][30] 

In patients who underwent resection, the 5-year survival rates for stages I, II, III, and IV were 89.9%, 82.6%, 75.8%, and 56.9%, respectively.[31] A recent study on functional NETs found that the stage of the disease, tumor grade, age of the patient, and surgical intervention were significant prognostic factors. In contrast, the tumor site and subtype had no impact on survival.[32]

Complications

Systemic complications include diabetes mellitus, cholelithiasis, iron deficiency anemia, macrocytic anemia, deficiencies of fat-soluble vitamins A, D, E, and K, manifesting as night blindness, osteopenia, and bleeding. Diabetes is usually mild, and ketoacidosis is rare. Patients with diabetes are treated with diet, oral hypoglycemic agents, or small doses of insulin, which may occasionally be required.[33] Even in the absence of cholelithiasis, prophylactic cholecystectomy is often performed during the initial surgical exploration due to the high risk of gallstone formation, particularly in patients who are candidates for somatostatin analog therapy.[34] Locally, the tumor can lead to obstructive hyperbilirubinemia and gastrointestinal bleeding.