Current Diagnostics and Treatments for Pancreatic Neuroendocrine Tumors
October 17, 2022 - read ≈ 14 min
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
Pancreatic neuroendocrine tumors (PNETs) arise from endocrine cells, sometimes referred to as islet cells, within the pancreas. The hormone producing islet cells cluster into small groups, known as islets of Langerhans, or simply islets, throughout the pancreas. The hormones produced by islet cells include glucagon, insulin, somatostatin, pancreatic polypeptides and ghrelin.
When tumors arise from one of these cells, they are referred to as PNETs. PNETs are relatively rare, accounting for only 1-2% of all pancreatic neoplasms. The incidence of PNETs has been increasing throughout the years. This is thought to be due to an increase in the incidental identification of PNETs discovered on cross-sectional imaging solicited for unrelated reasons. Most PNETs are slow-growing but do have malignant potential.
PNETs can either be functional or nonfunctional. Functional PNETs are associated with hormone-related syndromes secondary to secretion of a specific hormone derived by the primary islet cell that has transformed and expanded into the PNET. Nonfunctioning PNETs may still have hormonal activity, but do not secrete a high enough concentration of hormone to create a clinically relevant syndrome. Nonfunctional tumors constitute 60% to 90% of all PNETs.
Despite making up the majority of PNETs, non-functional PNETs tend to be diagnosed at a later stage than functional tumors. This is thought to be due to their indolent nature, lack of associated clinically detected hormonal syndrome, and the slow onset of symptoms. While most PNETs are sporadic, germline mutations can lead to well-described genetic syndromes, including Von Hippel-Lindau (VHL) syndrome, neurofibromatosis type I (NF1), and tuberous sclerosis. The most recognized hereditary endocrinopathy is multiple endocrine neoplasia type 1 (MEN1), in which 80-100% of individuals with this endocrinopathy develop a PNET.
Non-Functional Pancreatic Neuroendocrine Tumors
Non-Functional PNETs do not elicit hormonal syndromes. Therefore, they can be asymptomatic or have non-specific symptoms. The most common symptoms include abdominal pain, weight loss, anorexia and nausea with 35% to 78% of individuals presenting with abdominal pain, 20% to 35% with weight loss, and approximately 45% of individuals with anorexia and nausea. Less common symptoms include obstructive jaundice (17% to 50%), intra-abdominal hemorrhage (4% to 20%) or a palpable mass (7% to 40%).
Metastatic Pancreatic Neuroendocrine Tumors
The most common site of metastasis is the liver. As there is a lack of discernible symptoms, these PNETS are often diagnosed in late stages of the disease. Of all PNETs, 32% to 73% are identified to be metastatic at the time of diagnosis. Treatment algorithms are outlined below.
Functional Pancreatic Neuroendocrine Tumors
Functional PNETs are defined by their associated hormonal syndromes. Insulin producing tumors, otherwise known as insulinomas, produce symptoms such as confusion, episodic hypoglycemia, visual changes, unusual behavior, palpitations, abnormal sweating, coma, seizures and tremulousness. Gastrin producing neoplasms create a syndrome known as Zollinger-Ellison syndrome. The classical presentation of Zollinger-Ellison syndrome include recurring peptic ulcers in the distal duodenum and proximal jejunum.
Glucagonoma Syndrome is caused by glucagon producing islet tumors and commonly presents with an entity known as necrolytic migratory erythema. The common presentation of necrolytic migratory erythema includes bullous lesions that form from red papules along the extremities, perioral regions, and pregenital regions. Other common symptoms of glucagonoma syndrome include weight loss, diabetes mellitus, deep vein thrombosis, depression, and chronic diarrhea. Watery diarrhea, hypokalemia, and achlorhydria are symptoms of VIPomas, which are hypersecretions of a vasoactive intestinal peptide. 
The diagnosis of PNETs tends to be delayed due to the ambiguity of symptoms one may experience. In order to accurately diagnose PNETs, imaging and histological evidence from a biopsy are required. Hormonal testing is required if there is clinical suspicion based on history. Computerized tomography (CT) is the gold standard imaging study for PNETs. The pancreas should be examined with intravenous iodinated contrast typically utilizing a specialized pancreas protocol CT which includes imaging in three phases, early arterial phase, later arterial phase, which provides the best imaging of the pancreatic parenchyma, and venous phase, which provides optimal liver enhancement.[13,14] Due to the differences between the three phases, tumors in the pancreas are primarily detected during the later arterial and venous phases, using slices that are of 0.5mm thickness. CT has been found to have a specificity of 96% and a sensitivity of 73% for the diagnosis of PNET.
Another useful tool is magnetic resonance imaging (MRI), as its ability to differentiate structures based on signal intensity characteristics distinguishes normal pancreatic tissue from cancerous tissue. MRI is especially helpful in detecting liver metastases.
Localization of PNETs with the method listed above has a relatively high failure rate. The gold standard for both biopsy and histological diagnosis is endoscopic ultrasound, as this method is very sensitive to PNETs.  A helpful tool is somatostatin receptor scintigraphy. The somatostatin analog of choice is Gallium- 68. A 68-Gallium DOTATATE PET-CT scan allows for clearer imaging and higher spatial resolution when compared to other forms of imaging for both poorly- and well-differentiated tumors.
The American Joint Committee on Cancer (AJCC) 8th Edition Clinical Staging Classification for Pancreatic Neuroendocrine Tumors is broadly utilized for the staging of PNETs and is shown in Table 1. The AJCC TNM system, which incorporates the size and location of the tumor (T), presence of cancer in the lymph nodes (N), and if the tumor has metastasized to more distant areas (M).
|T1: Tumor limited to the pancreas less than or equal to 2cm||N0: No regional lymph node metastasis||M0:No distant metastasis|
|T2: Tumor limited to the pancreas 2-4 cm||N1: Regional lymph node metastasis||M1: Distant metastasis|
|T3: Tumor limited to the pancreas, > 4 cm, or invading the duodenum or common bile duct||M1a: Metastasis confined to liver|
|T4: Tumor invades adjacent structures||M1b: Metastasis in at least one extrahepatic site|
|M1c: Both hepatic and extrahepatic metastasis|
T1, N0, M0
|Tumor is less than 2 cm and still confined to the pancreas|
T2, N0, M0 T3, N0, M0
|Tumor is between 2 to 4 cm and confined to the pancreas|
Tumor is greater than 4cm and is either confined the pancreas or has spread to the duodenum or common bile duct
T4, N0, M0 Any T, N1, M0
|The tumor has grown into neighboring organs/nearby large blood vessels but has not spread to lymph nodes or distant parts of the body.|
Tumor has spread to nearby lymph nodes but is not in distant regions of the body
Any T, any N, M1
|The tumor has spread to distant parts of the body|
The grading system is defined by proliferative rate and differentiation quality. The grading schema prior to 2017 defined all well-differentiated tumors as NET-G1 or NET-G2. Poorly differentiated tumors were defined as NET-G3. It was later clarified that some G3 tumors were well-differentiated and had a relatively better prognosis than those with poorly-differentiated histology. Thus, the updated grading classification accounts for poorly differentiated and well-differentiated tumors. The grading system that is used in AJCC Staging is from the World Health Organization (WHO). The grading system for PNETs has vastly changed in the last few decades. The most current edition is the WHO 2017/2019 system, which is shown in Table 2.
|NET-G1: Well-differentiated, mitotic count < 2/2 mm2, Ki-67 ≤ 2%|
|NET-G2: Well-differentiated, mitotic count 2-20/2 mm2, Ki-67 3%-20%|
|NET-G3: Well-differentiated, mitotic count > 20/2 mm2, Ki-67 > 20%|
|NEC-G3: Poorly differentiated, mitotic count > 20/2 mm2, Ki-67 > 20%|
Resectable Pancreatic Neuroendocrine Tumors
For patients whose tumors are resectable, surgery should be the primary treatment. The surgery of choice is dependent on the location of the tumor. For tumors in the neck, body or tail of the pancreas, a subtotal or distal pancreatectomy is the preferred option. A splenic-sparing distal pancreatectomy may be an option for insulinomas and those with very low-grade malignant disease, although the latter is controversial. Enucleation or central pancreatectomy may be acceptable procedures for insulinomas depending on the location of the tumor and its relation to the pain pancreatic duct. However, in general, subtotal and distal pancreatectomy with splenectomy is the primary choice of resection for PNETs due to the incidence of lymph node metastases.  For tumors found in the head and uncinate process of the pancreas, a pancreaticoduodenectomy, well known as a Whipple procedure, is the mainstay of care. [21,22]
Per recently published guideless, all resectable functional PNETS should undergo surgical resection due to their associated hormonal syndromes. The guidelines published by the North American Neuroendocrine Tumor Society express that nonfunctional PNETs under 1cm that are asymptomatic can be observed without promptly planning for resection. These patients should undergo annual surveillance with cross-sectional imaging to ensure the PNET does not increase in size over time. For asymptomatic, nonfunctional PNETs that are between 1 to 2 cm in size, recommendation of resection needs to be based on individual factors, with resection considered for those PNETs closer to 2 cm in size, as these patients have a known incidence of nodal metastases.
In general, for those with appropriate performance status, all PNETs 2 cm in size or greater should undergo surgical resection, as these PNETs have a higher incidence of nodal metastases and propensity for systemic progression.
Advanced Pancreatic Neuroendocrine Tumors
When possible, treatment of metastatic PNETs involves resection of the primary tumor, involved lymph nodes, and metastasis.  This is typically beneficial in patients with lower grade disease. If liver metastases are resectable, partial hepatectomy should be conducted prior to pancreatic resection to avoid hepatic abscess formation.  A first-line therapy for metastatic PNETs is octreotide, which is a somatostatin analog pharmaceutical.
For well-differentiated tumors, agents such as mammalian target of rapamycin (mTOR) inhibitor, everolimus, and tyrosine kinase inhibitor, sunitinib, have been shown to increase progression-free survival duration for patients. For poorly differentiated tumors, chemotherapy is the primary form of treatment.  For tumors that progress despite initial treatment, multiple systemic treatments are available with varying efficacy, such as peptide receptor radioligand therapy (PRRT), chemotherapy, everolimus, and sunitinib.  PRRT uses somatostatin analogs that are radiolabeled to target PNETs that cannot be surgically removed. 
Hormonal Secretion Symptoms
In order to treat hypoglycemia associated with insulinomas, frequent meals and diazoxide can prevent insulin release.  Everolimus has also been shown to reduce hypoglycemia in patients with insulinomas.  For patients with Zollinger-Ellison syndrome, proton pump inhibitors or high, frequent doses of Histamine H2 receptor antagonists can be used to prevent hypersecretion of gastric acid.  For treatment of VIPomas, somatostatin analogs and electrolyte replacement are recommended. Somatostatin analogs are also the treatment of choice for glucagonomas.
The medical treatment of PNETs is rapidly changing. While predominantly an indolent disease, PNETs can also be aggressive depending on their histology. The lack of recognizable symptoms allows for late state diagnosis in this tumor type. Several diagnostic methods and various forms of treatments are currently available, which have changed the landscape for the management of PNETs.
- Pancreatic neuroendocrine tumor. Johns Hopkins Medicine. (2019, November 19). Retrieved May 18, 2022, from https://www.hopkinsmedicine.org/health/conditions-and-diseases/pancreatic-cancer/islet-cell-carcinoma
- Da Silva Xavier G. (2018). The Cells of the Islets of Langerhans. Journal of clinical medicine, 7(3), 54. https://doi.org/10.3390/jcm7030054
- Strosberg, J. R. (n.d.). Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms. UpToDate. Retrieved May 18, 2022, from https://www.uptodate.com/contents/classification-epidemiology-clinical-presentation-localization-and-staging-of-pancreatic-neuroendocrine-neoplasms#!
- Key statistics for pancreatic neuroendocrine tumor. American Cancer Society. (n.d.). Retrieved May 18, 2022, from https://www.cancer.org/cancer/pancreatic-neuroendocrine-tumor/about/key-statistics.html
- Pancreatic neuroendocrine tumors: biology, diagnosis, and treatment Ro, C., Chai, W., Yu, V. E., & Yu, R. (2013). Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment. Chinese journal of cancer, 32(6), 312–324. https://doi.org/10.5732/cjc.012.10295
- Falconi, M., Eriksson, B., Kaltsas, G., Bartsch, D. K., Capdevila, J., Caplin, M., Kos-Kudla, B., Kwekkeboom, D., Rindi, G., Klöppel, G., Reed, N., Kianmanesh, R., Jensen, R. T., & Vienna Consensus Conference participants (2016). ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology, 103(2), 153–171. https://doi.org/10.1159/000443171
- Ito, T., Igarashi, H. & Jensen, R.T. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances. J Gastroenterol 47, 941–960 (2012). https://doi.org/10.1007/s00535-012-0642-8
- Shin, J. J., Gorden, P., & Libutti, S. K. (2010). Insulinoma: pathophysiology, localization and management. Future oncology (London, England), 6(2), 229–237. https://doi.org/10.2217/fon.09.165
- Epelboym, I., & Mazeh, H. (2014). Zollinger-Ellison syndrome: classical considerations and current controversies. The oncologist, 19(1), 44–50. https://doi.org/10.1634/theoncologist.2013-0369
- Sandhu S, Jialal I. Glucagonoma Syndrome. [Updated 2022 Mar 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519500/
- Sandhu S, Jialal I. ViPoma. [Updated 2022 Mar 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507698/
- Kartalis, N., Mucelli, R. M., & Sundin, A. (2015). Recent developments in imaging of pancreatic neuroendocrine tumors. Annals of gastroenterology, 28(2), 193–202.
- Tempero, M. A., Arnoletti, J. P., Behrman, S., Ben-Josef, E., Benson, A. B., 3rd, Berlin, J. D., Cameron, J. L., Casper, E. S., Cohen, S. J., Duff, M., Ellenhorn, J. D., Hawkins, W. G., Hoffman, J. P., Kuvshinoff, B. W., 2nd, Malafa, M. P., Muscarella, P., 2nd, Nakakura, E. K., Sasson, A. R., Thayer, S. P., Tyler, D. S., … NCCN Pancreatic Adenocarcinoma (2010). Pancreatic adenocarcinoma. Journal of the National Comprehensive Cancer Network : JNCCN, 8(9), 972–1017. https://doi.org/10.6004/jnccn.2010.0073
- Murphy, A. (2021, November 17). Portal venous phase. Radiology Reference Article | Radiopaedia.Org. https://radiopaedia.org/articles/portal-venous-phase?lang=us
- Chaudhary, V., & Bano, S. (2011). Imaging of the pancreas: Recent advances. Indian journal of endocrinology and metabolism, 15(Suppl 1), S25–S32. https://doi.org/10.4103/2230-8210.83060
- Tamm, E. P., Bhosale, P., Lee, J. H., & Rohren, E. M. (2016). State-of-the-art Imaging of Pancreatic Neuroendocrine Tumors. Surgical oncology clinics of North America, 25(2), 375–400. https://doi.org/10.1016/j.soc.2015.11.007
- Michelle A Anderson, Steven Carpenter, Norman W Thompson, Timothy T Nostrant, Grace H Elta, James M Scheiman, Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas, The American Journal of Gastroenterology, Volume 95, Issue 9, 2000, Pages 2271-2277, ISSN 0002-9270, https://doi.org/10.1016/S0002-9270(00)01272-7.
- Pancreatic Neuroendocrine Tumor Stages. (2018, October 30). American Cancer Society. https://www.cancer.org/cancer/pancreatic-neuroendocrine-tumor/detection-diagnosis-staging/net-staging.html
- Ma, Z. Y., Gong, Y. F., Zhuang, H. K., Zhou, Z. X., Huang, S. Z., Zou, Y. P., Huang, B. W., Sun, Z. H., Zhang, C. Z., Tang, Y. Q., & Hou, B. H. (2020). Pancreatic neuroendocrine tumors: A review of serum biomarkers, staging, and management. World journal of gastroenterology, 26(19), 2305–2322. https://doi.org/10.3748/wjg.v26.i19.2305
- Michele Orditura, Angelica Petrillo, Jole Ventriglia, Anna Diana, Maria Maddalena Laterza, Alessio Fabozzi, Beatrice Savastano, Elisena Franzese, Giovanni Conzo, Luigi Santini, Fortunato Ciardiello, Ferdinando De Vita, Pancreatic neuroendocrine tumors: Nosography, management and treatment, International Journal of Surgery, Volume 28, Supplement 1,2016, Pages S156-S162,ISSN 1743-9191
- Roshdy, S., Hussein, O., Abdallah, A., Abdel-Wahab, K., & Senbel, A. (2015). Surgical management of adenocarcinoma of the pancreatic uncinate process in a cancer hospital in egypt. Clinical medicine insights. Gastroenterology, 8, 1–6. https://doi.org/10.4137/CGast.S20650
- Whipple procedure – Mayo Clinic. (2020, June 3). Whipple Procedure. Retrieved June 13, 2022, from https://www.mayoclinic.org/tests-procedures/whipple-procedure/about/pac-20385054#:%7E:text=A%20Whipple%20procedure%20%E2%80%94%20also%20known,pancreas%2C%20intestine%20and%20bile%20duct.
- Howe, J. R., Merchant, N. B., Conrad, C., Keutgen, X. M., Hallet, J., Drebin, J. A., Minter, R. M., Lairmore, T. C., Tseng, J. F., Zeh, H. J., Libutti, S. K., Singh, G., Lee, J. E., Hope, T. A., Kim, M. K., Menda, Y., Halfdanarson, T. R., Chan, J. A., & Pommier, R. F. (2020). The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors. Pancreas, 49(1), 1–33. https://doi.org/10.1097/MPA.0000000000001454
- Altimari, M., Abad, J., & Chawla, A. (2021). The role of oncologic resection and enucleation for small pancreatic neuroendocrine tumors. HPB : the official journal of the International Hepato Pancreato Biliary Association, 23(10), 1533–1540. https://doi.org/10.1016/j.hpb.2021.03.005
- Debnath D, Cheriyath P. Octreotide. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544333/
- Uptodate: Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion. UpToDate. (n.d.). Retrieved May 25, 2022, from https://www.uptodate.com/contents/metastatic-well-differentiated-pancreatic-neuroendocrine-tumors-systemic-therapy-options-to-control-tumor-growth-and-symptoms-of-hormone-hypersecretion#!
- lavio Forrer, Roelf Valkema, Dik J. Kwekkeboom, Marion de Jong, Eric P. Krenning, Peptide receptor radionuclide therapy, Best Practice & Research Clinical Endocrinology & Metabolism, Volume 21, Issue 1, 2007, Pages 111-129, SSN 1521-690X,
- Ito, T., Igarashi, H., & Jensen, R. T. (2012). Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best practice & research. Clinical gastroenterology, 26(6), 737–753. https://doi.org/10.1016/j.bpg.2012.12.003