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What Are Pancreatic Neuroendocrine Tumors (PNETs) and Are They Cancer?

Suggested Response to the Patient

Pancreatic tumors are classified by the pancreatic cell of origin from which the tumor arose [1]. The pancreas contains multiple nests of endocrine cells known as the islet cells of Langerhans. These islets are found scattered throughout the pancreas. Individual cell types secrete specific hormones; for example, beta cells produce insulin whereas alpha cells produce glucagon. Tumors originating from those endocrine cells, once termed “islet cell tumors ”, are now referred to as neuroendocrine tumors of the pancreas (or pancreatic neuroendocrine tumors [PNET]).

While all adenocarcinomas of the pancreas are considered malignant (cancer is a synonym for malignant), in order to consider a PNET malignant, it must demonstrate metastatic spread to regional lymph nodes or distant sites. Except for sporadic insulinomas which are isolated to the pancreas at the time of diagnosis (and are uniformly benign with no ability to metastasize), all other PNETs, if given enough time, will likely demonstrate malignant behavior. However, non-metastatic PNETs can be graded in terms of their biological aggressiveness (potential for metastatic behavior) [2]. PNETs have a wide range of clinical behaviors and the prognosis can be multifactorial, relating to the site of origin, functional status and specific tumor characteristics [3]. Due to this variability, a uniform pathologic classification was published by the World Health Organization in 2010 (Table 7.1). It was based on tumor characteristics including grade and Ki-67 value of the primary tumor; the latter being a measure of tumor proliferation [3–5]. Tumors were classified into three broad categories based on their malignant potential/prognosis: benign/uncertain , low , and high malignant potential . Such a classification is commonly referred to as well-differentiated endocrine tumors, well-differentiated endocrine carcinomas, and poorly differentiated endocrine carcinomas [4]. Risk factors of aggressiveness include size, degree of cell proliferation, whether or not the tumor has invaded surrounding structures or blood vessels and the presence of tumor spread to distant organs [5, 6].

Table 1 Table 7.1 The World Health Organization classification of PNETs
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Brief Review of the Literature

Approximately 49,000 people were diagnosed with pancreas cancer in the USA in 2014. However, only 2–4 % of those had a PNET, for an incidence of 1–2/100,000 people [7, 8]. PNETs may be sporadic in inheritance or less commonly, run in families. Multiple Endocrine Neoplasia type 1 (MEN1 ) is a genetic syndrome that results in tumors of the pituitary gland, parathyroids, and the pancreas. PNETs can also occur in (1) Von Hippel–Lindau (VHL) syndrome which also includes tumors of the central nervous system, the kidneys and the adrenals, (2) Tuberous Sclerosis Complex (TSC), a disease which also includes tumors in the brain, kidneys, skin, and eyes, and (3) Neurofibromatosis type 1 (NF-1), a condition where tumors grow along the nerves in the skin, brain, and internal organs.

PNETs are classified according to their ability to secrete hormones and, if they do, the type of hormone that is produced. Tumors that do not produce hormones (nonfunctional) are the most common type and constitute 70–80 % of PNETs. Most of the symptoms that nonfunctional PNETs cause are due to the local effects of the tumor itself [9]. In contrast, functional tumors, which make up 20–30 % of PNETs, overproduce specific hormones [1]. For example, endocrine cells of the pancreas produce insulin and glucagon, two hormones involved in regulating blood sugar, in addition to many other digestive and metabolic properties. Gastrin, somatostatin, and vasoactive intestinal peptide (VIP) are three other hormones also produced by endocrine cells of the pancreas. Tumors originating from these cells are called insulinoma, glucagonoma, gastrinoma, somatostatinoma, and VIPoma, respectively (Table 7.2) [7].

Table 2 Table 7.2 Functional classification of PNETs
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How Are PNETs Diagnosed?

Diagnosis of PNETs includes two general objectives: a biochemical evaluation and localization of the tumor. Neuroendocrine tumors of the pancreas have a broad range of clinical presentations. Functional tumors usually present with signs and symptoms of overproduction of a specific hormone. Nonfunctional tumors are either found incidentally on imaging studies done for other reasons or cause local symptoms due to compression/obstruction of other organs or blood vessels. Patient history and physical examination are the first and one of the most important parts of the initial patient encounter. Nonspecific symptoms of abdominal pain, fatigue and weakness may be present but usually the patient is asymptomatic or has just recently become symptomatic. A high index of suspicion for familial syndromes is imperative in all patients diagnosed with a PNET and in patients with a positive family history, evaluation for the associated tumor constellation should be undertaken.

Brief Review of the Literature

Functional Tumors

The most common functional PNET is an insulinom a which is usually sporadic in inheritance and benign (90 %). Rarely, insulinomas are part of the MEN-1 syndrome (pancreas, pituitary, parathyroid) in which case they are usually multifocal within the pancreas. Patients usually present with signs and symptoms of hypoglycemia caused by high insulin levels. These “neuroglycopenic” symptoms may include weakness, excessive perspiration, palpitations, altered mental status, seizures, and in severe cases, coma [10]. A 72-h controlled fast measuring blood glucose and insulin levels drawn at regular intervals is often diagnostic for insulinomas. One has to always exclude the rare circumstance where a patient has factitiously low blood glucose levels due to administration of exogenous insulin or diabetes medications of the sulfonylurea class [11]. Insulin is synthesized as a larger molecule called proinsulin. The latter is cleaved and processed inside beta cells into insulin and C-peptide. A high level of insulin and absence of C-peptide on blood tests is consistent with factitious hypoglycemia, usually found in health care workers who have access to insulin. Insulinomas are usually hypervascular, well-circumscribed, solitary masses on axial imaging and can be found in any part of the pancreas. They are usually small in size and are less than 2 cm in the majority of the cases [12, 13]. They can be multifocal in MEN-1 syndrome, thus the importance of examining the pancreas for other smaller lesions at the time of initial diagnostic imaging (and the importance of knowing whether the patient does or does not have MEN1 before operation).

Gastrinoma is the second most common PNET and the most common PNET found in MEN-1 patients; one third of gastrinoma patients have a hereditary endocrinopathy. High blood levels of gastrin are seen in Zollinger–Ellison Syndrome, in which patients present with intractable ulcers. Excessive stimulation of parietal cells in the body of the stomach by gastrin leads to high levels of acid secretion. These ulcers tend to be hard to treat, occur in young patients and arise in unusual locations (jejunal) [14]. Associated symptoms include abdominal pain, nausea and diarrhea, and weight loss. Gastrinomas can be diagnosed by measuring serum levels of gastrin with and without stimulation by the hormone secretin. Secretin, under normal circumstances, suppresses gastrin secretion; however, in gastrinoma patients, it stimulates gastrin production to very high levels. Gastrinomas are historically known to be found in an area referred to as the “gastrinoma triangle,” especially when unifocal and sporadic in nature. The gastrinoma triangle is anatomically defined by the junction of the cystic and common hepatic ducts superiorly, the junction of the neck and body of the pancreas medially, and the area between the second and third portion of the duodenum inferiorly [15].

Glucagonomas secrete high levels of glucagon. Typical clinical manifestations include new onset diabetes, diarrhea, deep vein or arterial thrombosis, weight loss, abdominal pain, depression, and dermatitis. Approximately 70 % of glucagonoma patients have a characteristic rash referred to as “necrolytic migratory erythema,” an eruption that occurs in areas of friction on the body such as buttocks, groin and feet [16]. Patients with glucagonoma present with elevated blood glucose and glucagon levels, anemia, and low protein levels as these proteins are used to make glucose. Most glucagonomas are found in the body and tail of the pancreas and tend to be large in size.

Somatostatinomas are rare PNETs and are usually malignant. Somatostatin is known to be the universal inhibitor hormone. It inhibits actions of insulin and gastrin, and pancreatic exocrine enzymes, leading to high blood sugar levels, gallstones, and malabsorption of ingested food leading to diarrhea [17]. Somatostatinomas tend to be large and are located mainly in the pancreatic head [12].

VIP tumors are also rare PNETs which are mostly benign and solitary. Excess VIP hormone secretion is associated with a cluster of symptoms that have been named Verner–Morrison syndrome. This syndrome includes diarrhea, low serum potassium and low gastric acid secretion [18]. The majority of VIPomas are found in the tail of the pancreas [12].

Nonfunctional Tumors

Nonfunctional PNETs do not produce clinically active hormones; however, they are known to secrete peptides such as pancreatic polypeptide, neurotensin, chromogranin A, and neuron-specific enolase. Chromogranin A, in particular, can be clinically helpful as a tumor marker to guide treatment and signal recurrence and disease progression; it is present in 60–100 % of nonfunctioning PNETs [19–21]. Any PNET can cause signs and symptoms of local tumor compression of adjacent organs depending on the size and the location of the primary tumor. Tumors of the head of the pancreas can cause obstruction of the common bile duct which can lead to jaundice, pruritus, acholic stools, and dark urine. Tumors of the body and tail of the pancreas often grow to reach large sizes before causing local symptoms.

Tumor localization and extent of disease are key to the diagnosis and treatment of patients with PNETs. Localized, unifocal disease is treated differently than multifocal and metastatic disease. Traditional imaging techniques using ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), or radiolabeled octreotide scans have been the mainstay for localizing PNETs. New endoscopic and nuclear imaging technologies are also now part of the available armamentarium. Upper endoscopy is augmented by the use of an ultrasound probe on the tip of the endoscope, otherwise termed an “endoscopic ultrasound” (EUS). This can provide improved visualization of the tumor and surrounding lymph nodes compared to transabdominal ultrasound. EUS is especially useful for detection of small tumors and/or multiple tumors in patients with MEN1. Additionally, when indicated, EUS can be utilized to perform a fine needle aspiration (FNA). The aspirate (EUS-FNA biopsy) is considered a biopsy of the tumor and has a high sensitivity for diagnosing a PNET [22, 23]. Transabdominal ultrasound (U/S) detects PNETs only 40 % of the time as it is not very sensitive for detecting small tumors or regional lymph node metastases, but it is highly specific for PNETs if found [12]. PNETs appear as a well-defined circular mass that is darker than the surrounding pancreas and is well vascularized when Doppler mode is used [24].

Computed tomography (CT) and magnetic resonance imaging (MRI) are comparable and identify at least 70–75 % of pancreatic neuroendocrine tumors; a number which is increasing with improved technology. They have the advantage of detecting extrapancreatic lesions (liver metastases) with an 85–90 % detection rate. Neuroendocrine tumors are hypervascular and therefore best detected during the early arterial phase of a dual phase CT scan, when the tumor-to-pancreas contrast is greatest [12, 23, 25]. Nuclear medicine imaging, such as octreotide scans, play a key role in detection of neuroendocrine tumors due to a distinct feature that up to 80 % of these tumors express somatostatin receptors [12, 26]. Figures 7.1 and 7.2 contain classic images of a PNET by CT, MRI, and Octreotide scan of a patient treated at our institution for a pancreas body neuroendocrine tumor.

Fig. 7.1
figure 1

Axial sections of CT scan of a pancreas body neuroendocrine tumor (white arrow) seen enhancing in early arterial phase in (a), with faded enhancement in the venous phase in (b). The same tumor is seen in a coronal section of the arterial phase in (c), angiographic 3D reconstruction of the well vascularized tumor seen in (d)

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Fig. 7.2
figure 2

Axial MRI sections of the same tumor seen in Fig. 7.1, showing increased signal intensity in T2-weighted images in (a), and T1-weighted images in (b). Octreotide scan images are seen alone (c) or fused (d), with CT scan that clearly show tumor radiolabel uptake

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How Long Will I Survive? Will I Need Chemotherapy?

Prognosis and Treatment Options for Pancreatic Neuroendocrine Tumors

Suggested Response to the Patient

There has been a tremendous expansion in the available therapies for PNETs over the past decade, in parallel with an increase in the incidental radiological detection of these tumors in younger patients [27, 28]. Relative to pancreatic adenocarcinoma, patients with PNETs are usually long-lived (5-year overall survival of 80 %) [29]. The goal, after initial diagnosis, is to classify and stage each patient’s tumor in order to assign the optimal treatment strategy. These cases are usually discussed at multidisciplinary conferences where physicians from multiple disciplines establish the appropriate personalized treatment. Disciplines include surgery, gastroenterology, radiology, medical and radiation oncology, and transplantation.

Brief Review of the Literature

Symptom Control

In patients with functional PNETs, treatment usually begins by alleviating symptoms due to excess hormone production. Insulinoma treatment includes avoiding episodes of serious hypoglycemia; this can be done with serial glucose monitoring during the day, consumption of multiple small meals, and the use of anti-insulin medications such as Diazoxide, Verapamil, or Dilantin [13]. Medical treatment of gastrinomas is geared toward suppression of gastric acid secretion, and this is successfully done with high dose proton-pump inhibitors. For patients with VIPoma or glucagonomas, diarrhea, elevated glucose levels, and electrolyte abnormalities are treated with supportive care that typically includes insulin, repletion of fluid and electrolyte abnormalities, and close monitoring of nutritional status. Somatostatin analogues (SSA) such as Octreotide have been the mainstay of symptom control for patients with PNETs. Octreotide not only inhibits hormone secretion from these tumors, but also has a tumoristatic effect [30, 31]. Recent trials proved the effectiveness of SSAs for treatment of locally advanced and metastatic PNETs and this has been incorporated into national and international guidelines [32–34]. Local mass effect caused by PNETs in the pancreatic head may cause biliary obstruction, resulting in jaundice and pruritus. Symptomatic relief of these symptoms can be achieved by stenting the obstruction open using endoscopic or percutaneously placed stents [35–37].

Treatment

There has been a rapid expansion in the armamentarium of treatment modalities that can be offered to PNET patients in the last decade. Medical, interventional, and surgical options are available; however, consensus is still lacking on proper treatment sequencing [28]. The key step is to determine the clinical and biological information of the primary tumor and personalize treatment accordingly [38]. Workup is usually started by ruling out metastatic disease. EUS with fine needle aspiration biopsy of the tumor is done to assess for tumor grade and Ki-67 status. The Ki-67 status of the tumor is critically important for the determination of proper treatment.

Since surgery is the only known curative treatment, the next step in management is determining surgical resectability of the tumor. In solitary, low grade tumors, confined to the pancreas, minimally invasive surgery is the current state-of-the-art approach. Laparoscopic and robotic-assisted approaches are now commonly used supported by multiple studies which have proved safety and efficacy [39]. The goal of treatment is to remove the tumor while preserving as much of the pancreas as possible; otherwise known as a “parenchymal preservation” strategy. This allows preservation of endocrine and exocrine function of the pancreas when possible [40–42]. Depending on the location of the tumor and the status of the rest of the pancreas, surgical options may include enucleation, central pancreatectomy, distal pancreatectomy, pancreaticoduodenectomy (Whipple procedure), or total pancreatectomy. Complete surgical resection is also associated with prolonged survival even in the setting of metastatic disease (when the primary and distant sites can all be surgically excised) [29, 43–46]. Unfortunately, a high percentage of patients present with extensive, unresectable tumors and the role of surgery is often limited to symptom control; in such patients, systemic therapy and sandostatin analogue therapy are often the initial choice of treatment [47–51]. Liver transplantation for PNETs is used infrequently, and is controversial [52].

Up to 85 % of patients with PNETs present with synchronous liver metastases or develop metachronous disease to the liver years after the primary tumor was removed [53]. In patients with unresectable, liver dominant disease, several other treatment modalities confer positive outcomes with modest side effects [54]. Liver metastases can be treated with trans-arterial embolization or chemo-embolization (TAE, TACE), radio-embolization, ablation, or in limited cases, external beam radiation [53–59]. TAE or TACE are based on the knowledge that these tumors are supplied by branches of the hepatic artery (rather than the portal venous system). Selective embolization of branches of the hepatic artery with small spheres, with or without chemotherapy is the basis of such procedures. Ablation techniques involve heat (radiofrequency or microwaves) or cold (cryotherapy) [48, 60–63]. Radiation can either be delivered transarterial (yttrium 90) or by external beam. The latter is usually reserved for isolated, unresectable tumors, in anatomically difficult locations that are not amenable to other techniques [64]. One interesting treatment option that is not yet available in the USA includes the use of radiolabeled somatostatin analogues. Radioactive molecules are attached to a somatostatin analogue which binds tumor cells and cytotoxicity is by means of radiation selectively delivered to those cells. This method avoids radiation to normal cells. This technique is referred to as peptide receptor radionuclide therapy (PRRT) [65, 66].

In patients with advanced PNETs, whether metastatic, unresectable, or high grade and poorly differentiated, several systemic therapies have been used. Conventional chemotherapy that included streptozocin (STZ), 5-fluorouracil (5-FU), and doxorubicin used to be the mainstay of treatment in this category of patients. These agents promote tumor cell death through interference with DNA synthesis. Although initially shown to be quite effective, response rates have not been as favorable in more recent reports [33, 34, 67]. New chemotherapeutic agents such as capecitabine and temozolomide have shown more promise with a radiological response rate of up to 70 %, and such agents have even been used to downstage metastatic dsisease for surgical resection [28, 68]. Capecitabine is processed in the liver to produce fluorouracil, a compound that inhibits DNA synthesis in tumor cells. Temozolomide is another cytotoxic agent that gets cleaved into an active metabolite causing tumor cell death through a process of DNA alkylation. In general, chemotherapy is reserved for inoperable disease or to downstage borderline resectable disease thereby facilitating a less difficult operation [67, 69].

Recently, several trials investigated and proved the efficacy of targeted therapies in patients with advanced PNETs. New agents target specific proteins made by PNETs. Of those, everolimus, which belongs to a class of drugs called inhibitors of the mammalian target of Rapamycin (mTOR), has been shown to slow disease progression [70–73]. Sunitinib has been shown to prolong survival by inhibiting vascular endothelial growth factor (VEGF) receptors [74, 75].

Conclusion

The incidence of neuroendocrine tumors of the pancreas is on the rise. PNETs have a wide variety of clinical presentations and biological behaviors. Whereas significant progress has been made in the understanding and classification of these tumors, consensus protocols for treatment sequencing are still somewhat poorly defined. Surgery is the only potentially curative therapy, however, most of these patients present with metastatic disease, and may require a combination of multiple modalities that include cytotoxic chemotherapeutic agents, targeted biological agents, and radio/chemo-embolization.