The pancreas is a gland that appears like a thin pear lying on its side behind the stomach and in front of the spine. It has four parts: the head (wider part of the gland), neck, body (middle section), and tail (narrow end). Physiologically, the pancreas has endocrine and exocrine cells. The endocrine cells release hormones like insulin and glucagon to regulate blood glucose. Clusters of these endocrine cells in the pancreas are also known as islets.
The exocrine cells release hormones into the small intestine to aid in the digestion of the food. These cells line the end of the ducts, which are present throughout the pancreas.
Tumors of neuroendocrine origin emerging in the pancreas or in proximity to the pancreas are described as pancreatic neuroendocrine tumors or islet cell tumors of the pancreas.
In the majority of cases, the pancreatic neuroendocrine tumors arise sporadically. However, in some cases, they arise as part of multiple endocrine neoplasia type 1 along with the tumors of the parathyroid and anterior pituitary. The disease is due to the inactivation of the Menin gene located on chromosome 11q13. Menin gene is a tumor suppressor gene. When pancreatic neuroendocrine tumors appear as a part of the MEN type 1, multiple pancreatic tumors can appear. They can also appear as a part of von Hippel Lindau disease, neurofibromatosis type 1, and tuberous sclerosis.
When the data of the incidence rate of neuroendocrine tumors from 1973 was compared with data from 2012, there was nearly a six times increase in incidence from 1.09 per 100,000 to 6.98 per 100,000. For gastropancreatic sites, the highest incidence was 3.56 per 100,000. On 1st January 2014, the limited-duration prevalence spanning 20 years for neuroendocrine tumors was 171,321 in the United States. The overall survival rates for all neuroendocrine tumors have been increasing when compared between periods of 2000-2004 with 2009-2012. The increase in overall survival rate for distant stage pancreatic neuroendocrine tumors, when compared between these two periods, was substantial (HR, 0.56; 95% CI, 0.44-0.70).
A-cells, B-cells, D-cells, D1-cells, and D2-cells are the normal types of islet cells of Langerhans in the pancreas. The normal function of A-cells is to secrete glucagon, B-cells is to secrete insulin, D-cells is to secrete somatostatin, D1-cells is to secrete a pancreatic polypeptide, and D2-cells is to secrete vasoactive intestinal peptide. Islet cell tumors secrete one or more than one of these substances in the majority of the cases. However, in some cases, they may secrete other substances like gastrin, which is normally produced by the fetal cells of the pancreas.
Islet cell tumors can be either functional (release hormones that can further produce symptoms) or nonfunctional (they do not produce any hormones). Nonfunctional tumors produce their symptoms due to mass effect. The common types of functional tumors are gastrinoma, insulinoma, glucagonoma, somatostatinoma, and VIPoma.
During the endoscopic ultrasound, fine-needle aspiration biopsy can help in diagnosing the islet cell tumor. Characteristic neuroendocrine chromatin, single plasmacytoid cells in the cytoplasm are the distinctive features of pancreatic neuroendocrine tumors on cytology. Positive staining to chromogranin A indicates the neuroendocrine nature of the tumor in the majority of the cases. Some high-grade neuroendocrine lesions can be negative for chromogranin A, especially neuroendocrine tumors, which are poorly-differentiated. When cases like this present, staining for Synaptophysin helps specify the nature of the lesion.
Non-functional pancreatic neuroendocrine tumors present late as they mostly produce mass effect symptoms. This late presentation leads to excessive growth or metastasis on presentation. They can present with jaundice, back pain, diarrhea, indigestion, abdominal pain, or a lump in the abdomen.
The presentation of functional neuroendocrine tumors depends on the specific type.
Gastrinoma is the type in which the tumor releases gastrin and its precursors i.e., progastrin. These substances copy the action of physiologically produced gastrin by the G-cells of the antrum. The most common presentation of gastrinoma is peptic ulcer. Moreover, 75 percent of the patient with gastrinoma have complaints of diarrhea. The suspicion for gastrinoma arises when a patient presents with multiple or resistant peptic ulcers.
Insulinoma presents with hyperinsulinemic hypoglycemia in patients. The disease is manifested as the Whipple triad. This includes symptoms of low blood glucose, along with the symptoms of hypoglycemia. Moreover, the symptoms should settle with glucose intake.
VIPoma in a patient can cause watery diarrhea, hypokalemia, and achlorhydria. This is called VIPoma syndrome or WDHA syndrome.
Glucagonoma can cause glucagonoma syndrome. This includes weight loss, anemia, diabetes mellitus, thromboembolism, neuropsychiatric symptoms, gastrointestinal disturbances, etc. Necrolytic migratory erythema is a characteristic rash that appears with glucagonoma. It appears as erythematous plaques with irregular borders. The center of the lesion forms a bulla. This bullae then erodes and crust, eventually leading to the healing of the center of the lesion.
Carcinoid syndrome is the prevalent feature in the carcinoid tumor of the pancreas. The main manifestations include cutaneous flushing, valvular disease, and diarrhea. Serotonin is produced by the tumor, which leads to this characteristic triad of symptoms.
Liver metastasis occurs in the majority of these cases. However, there have been few cases reported without any liver metastasis. Moreover, the absence of carcinoid syndrome does not rule out carcinoid tumors of the pancreas.
Due to the complex presentation of the pancreatic neuroendocrine tumors (PNETs), the diagnosis is mostly delayed. The precise diagnosis of the PNETs requires endocrine testing and evidence of the tumor through imaging. Moreover, histological findings of the tumors also play a major role in the whole process. The goal of the evaluation is to establish the nature of the PNETs, to gauge the tumor grade, identify primary and metastatic lesions, and to assess whether the tumor is functional or not.
Biochemical testing becomes an important modality in the evaluation of the tumor if functional PNETs are suspected. Biochemical testing is followed by imaging, endoscopy, and biopsy of the lesion. Biochemical testing is recommended in patients without suspicion of hormonal hypersecretion syndrome. The rationale behind this practice is that the patient may have subclinical secretion of the hormones. And in this case, the hypersecretion hormones can be used as tumor markers in subsequent evaluations. PNET markers include Chromogranin A (CGA), neuron-specific enolase (NSE), and pancreastatin are the most useful PNET markers. Since functional PNETs often produce pancreatic polypeptide, glucagon, gastrin, insulin, vasoactive intestinal polypeptide, and proinsulin, the fasting levels of these hormones should also be measured.
Evaluation of potential metastases to liver, pancreas, lymph nodes is done through magnetic resonance imaging (MRI) or computed tomography (CT) of the abdomen and pelvis. To evaluate the affinity of the tumor for somatostatin, nuclear imaging with octreotide is very helpful. It also detects any occult tumors which are often missed by anatomical imaging. Biopsy of liver masses is taken transcutaneously with ultrasound or CT guidance. Endoscopic ultrasound guidance is helpful when a biopsy of a pancreatic mass is required. The identification of nature and the grading of the neuroendocrine tumor relies solely on tumor biopsy. Moreover, immunocytochemical staining for hormones is also dependent on tumor biopsy.
In addition to positive imaging findings for a carcinoid tumor of the pancreas; one of the following is required to make a diagnosis of carcinoid type of pancreatic neuroendocrine neoplasm: Elevation of 5-hydroxyindoleacetic acid in the urine and/or detection of 5- hydroxytryptamine in the tissue sample or its elevation in the serum.
Even though the majority of the pancreatic islet cell cancers are indolent, an aggressive approach is preferred to the “wait-and-see” approach when dealing with them. The aggressive approach includes taking out the primary and metastatic tumors. However, the implementation of the aggressive approach requires a team comprised of multiple specialties to deal with pre and post-surgical management. The aggressive therapy for PNETs involves surgery, locoregional therapy followed by systemic therapy, and complication control.
The clinical cure for a non-metastatic primary lesion of PNET is surgical removal. If there are metastatic liver lesions of PNET, surgical debulking is an important treatment option to reduce the functional hormone secretion from the lesion as well as to reduce the mass effect of the tumor. Locoregional therapy for PNET liver metastasis can be achieved through microwave ablation, bland embolization, chemoembolization, radiofrequency ablation, radioactive polymer microspheres, and transcutaneous alcohol ablation.
Most patients have residual disease even after surgical and locoregional therapy; they require systemic therapy to deal with residual tumors. Functioning PNETs like VIPoma and glucagonoma are effectively managed with somatostatin analogs at this stage. Octreotide, lanreotide, and pasireotide are somatostatin analogs that are being used for this purpose. The role of somatostatin analogs in the management of nonfunctioning pancreatic tumors is controversial.
There are a few other causes that can mimic the imaging presentation of pancreatic neuroendocrine tumors. These include acinar cell carcinoma of the pancreas, solid pseudopapillary neoplasm of the pancreas, and pancreatoblastoma. The biopsy of the lesion is, therefore, the gold standard for diagnosing PNETs.
The phenomenon of delivery of radiotherapy to target somatostatin receptors in the malignant neuroendocrine tumor cells resulting in shrinkage of the tumor is peptide receptor radionuclide therapy (PRRT). The treatment with PRRT alleviation of symptoms in nearly 80%, control of the disease in about 78%, and partial to complete response in almost 59% of patients with metastatic functioning pancreatic neuroendocrine tumors.
The patients with recurrent, advanced, or metastatic pancreatic neuroendocrine tumors can often be poor candidates for surgical resection. This makes medical therapy the next best option for pancreatic neuroendocrine tumors. Medical therapy can be either symptom directed or for controlling the growth of the tumor.
Patients with gastrinoma often produce acid in high amounts, which requires the use of high dose proton pump inhibitors. For insulinoma, small meals with nutritional adjustments are required. Diazoxide is also used to suppress the secretion of insulin in such patients. Parenteral nutrition with the inclusion of vitamin supplementation is necessary for patients with glucagonoma.
Persistent diarrhea in carcinoid syndrome can be controlled with telotristat ethyl. It is a tryptophan hydroxylase inhibitor that decreases the bowel movements and the amount of 5-hydroxyindole acetic acid in urine.
The tumor growth has been effectively controlled to an extent with chemotherapy (temozolomide, capecitabine, streptozotocin, dacarbazine, oxaliplatin, 5-fluorouracil), somatostatin analogs (lanreotide and octreotide) and targeted molecular treatment (sunitinib, everolimus, etc.).
The secretion of a wide range of hormones is inhibited by somatostatin. Somatostatin analogs, like lanreotide and octreotide, have similar effects. Pancreatic neuroendocrine tumors express somatostatin receptors, especially somatostatin receptor type 2. These somatostatin analogs decrease the secretion of hormones by binding to somatostatin receptors in the tumor. As far as the antiproliferative efficacy of somatostatin analogs is concerned, the CLARINET trial confirmed it. The results showed a significant progression-free survival in the long term when lanreotide was used in patients with well-differentiated neuroendocrine tumors. However, there was no significant increase in overall survival among the patients treated with lanreotide.
Everolimus bind with the mammalian target of rapamycin (mTOR) to inhibit it. Sunitinib is a multiple receptor tyrosine kinase inhibitor. Both of these drugs are a second-line treatment for patients with progressive pancreatic neuroendocrine tumors. Both of the drugs have shown a significant increase in the progression-free survival and overall survival of the patients.
There are a number of cytotoxic chemotherapeutics agents like capecitabine, 5 fluorouracil (5-FU), oxaliplatin, streptozocin, dacarbazine, temozolomide. There is no accepted best cytotoxic agent. Moreover, these agents are often used in combinations like temozolomide-capecitabine, streptozocin with doxorubicin or with 5-FU, or a combination of streptozocin, 5-FU, and doxorubicin (FAS).
FAS combination had a response rate of 39%, which resulted in increased overall survival and progression-free disease. The chosen population was patients with metastatic or locally advanced pancreatic neuroendocrine tumors. A combination of 5-FU/streptozocin with bevacizumab showed overall survival at 24 months and progression-free survival at 23.7 months to be 88% in patients with metastatic or locally advanced pancreatic neuroendocrine tumors.
Temozolomide is an effective treatment both as a monotherapy or in combination with bevacizumab and capecitabine. A 70% objective response rate was reported when a combination of temozolomide and capecitabine (CAPTEM) was used in patients with pancreatic neuroendocrine tumors. This was a retrospective study conducted in 2011 and showed an overall survival of 92% and progression-free survival of 18 months at the endpoint of 2 years.
In 2006, the European Neuroendocrine Tumor Society (ENETS) adopted a TNM staging system for pancreatic neuroendocrine tumors. The American Joint Committee on Cancer (AJCC) did not have any specific TNM staging system for pancreatic neuroendocrine tumors until 2010. There are some differences between these two staging systems. The AJCC Tumor-Node-Metastasis staging system is:
Primary Tumor (T) Classification
Regional Lymph Nodes (N)
Distant Metastases (M)
TNM staging by ENETS is:
Primary Tumor (T) Classification
Regional Lymph Nodes (N)
Distant Metastases (M)
The details of TNM staging by AJCC and ENETS show major differences between the two systems.
Pancreatic neuroendocrine tumors generally have a better prognosis than adenocarcinoma of the pancreas. Metastasis of the tumor and incomplete resection of the tumor usually leads to a worse prognosis. Moreover, functional pancreatic endocrine tumors have a better prognosis than non-functional tumors.
Complications can arise directly due to the release of hormones from the tumors or due to the mass effect of the tumor. Recurrent pancreatitis, intestinal obstruction, and gastrointestinal bleeding can occur due to direct invasion by the tumor. Even varices can occur due to obstruction of the splenic vein by the tumor.
Carcinoid syndrome is associated with a certain complication known as a carcinoid crisis. The symptoms usually involve stupor, confusion, flushing, hyperthermia, cardiac arrhythmias, diarrhea, bronchospasm, and drastic fluctuations in blood pressure (usually hypotension accompanied by shock but sometimes hypertension can also occur). Various procedures are implicated in the precipitation of the carcinoid crisis. These include radiological procedures (like biopsies, embolization), anesthesia, chemotherapy, anesthesia, surgery, stress, or even abdominal palpation of the area where neoplasm is located. The treatment and prevention of the carcinoid crisis include the use of somatostatin analogs. However, there has been some controversy related to the efficacy of somatostatin analogs in such scenarios.
There are no environmental risk factors that affect an increase or decrease in the chances of developing pancreatic neuroendocrine tumors. However, there are certain syndromes in which there is a substantial risk of developing PNETs. These include multiple endocrine neoplasia type 1, Von Hippel Lindau syndrome, neurofibromatosis type 1, and tuberous sclerosis. Patients with these diseases should be educated about their increased risk of developing PNETs. If the patients are wary of the symptoms, they will heed professional intervention early on in the course of the tumor progression.
The diagnosis of the PNETs requires a thorough workup and a high suspicion level as far as the healthcare provider is concerned. Moreover, the treatment and management of pancreatic neuroendocrine tumors require a multidisciplinary team. Surgeons, oncologists, radiologists, endocrinologists, and nurses need to work as a team to provide ideal care to the patient.
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