Pancreatic neuroendocrine tumors: Classification, clinical picture, diagnosis, and therapy

Introduction

Neuroendocrine tumors (NETs) represent a group of heterogenous neoplasms that originate from the diffuse neuroendocrine cell system, most commonly arising in the lung or gastrointestinal (GI) tract. Although NETs represent a rarer group of neoplasms, NET incidence and prevalence continues to increase and NETs are now the second most prevalent GI cancer. Well-differentiated NETs can be subdivided largely based on their tissue of origin, with pancreatic neuroendocrine tumors (PNETs) representing those NETs that originate from endocrine tissue of the pancreas (i.e., islets of Langerhans).

PNETs are the second most common tumor arising from the pancreas. ^, A comprehensive PNET diagnosis relies on the evaluation of clinical symptoms, imaging, and histopathology. The management and treatment of PNETs can be challenging because of the heterogeneity in tumor behavior, as well as clinical presentation, with approximately 30% of PNETs presenting as functional tumors, producing clinical symptoms from hormone hypersecretion. Although many advanced PNETs can be monitored initially because of indolent growth patterns, with time the disease will require treatment; the decision to start a therapy occurs because of increasing clinical symptoms (from hormone secretion and/or tumor bulk), high tumor burden, and/or progressive disease while on observation. Treatment options for PNETs are multidisciplinary and include surgical resection, liver-directed therapies, and systemic treatments. For metastatic PNETs, treatment is almost always noncurative, and although survival for patients can often be measured on the order of years, most patients will die of the disease. ^, This chapter reviews the classification, clinical features, diagnosis, and treatment of PNETs.

Epidemiology

PNETs account for approximately 7% of all NETs and 1% to 2% of pancreatic tumors (see Chapters 59 and 61 ). The incidence of PNETs has risen over the past 30 years from 0.17 to 0.43 cases per 100,000 people. Males and females are affected equally. Most patients are diagnosed between the ages of 60 to 80 years. Approximately 5% of patients will have an underlying familial syndrome predisposing to PNET development, such as multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau (VHL), tuberous sclerosis (TS), or neurofibromatosis type I (NF1), and these patients tend to be diagnosed at a younger age. A family history significant for NET is the only well-established risk factor for PNET development ; risk factors for pancreatic adenocarcinoma, such as cigarette smoking, diabetes mellitus, chronic pancreatitis, and obesity, have not been found to be associated with the development of PNET.

Molecular biology and somatic alterations

Apart from the germline syndromes previously described, in recent years, understanding of the genetic basis of sporadic PNETs has advanced (see Chapter 9D ).

In one of the earliest studies, whole-exome sequencing was performed in 10 nonfamilial PNETs, and the most commonly mutated genes were screened in an additional 58 PNET specimens. In the tested tumors, an increased number of mutations were identified in chromatin remodeling genes (MEN1 , DAXX , ATRX), and in genes of the mammalian target of rapamycin (mTOR) pathway (notably in PTEN , TSC2 , and PIK3CA ).

Whole-genome sequencing was subsequently performed. In this analysis of 102 PNETs, somatic point and gene fusion mutations were observed in genes along four pathways (chromatin remodeling, DNA damage repair, mTOR, telomere maintenance). In addition, a larger than anticipated germline contribution was identified, with previously unreported germline mutations seen in DNA repair genes (MUTYH, CHEK2, and BRCA2).

Building on the findings from whole-exome and whole-genome sequencing, additional efforts have evaluated a role for genetic testing in the routine clinic setting. The benefit of next-generation sequencing (NGS) was assessed in 96 tumor samples from 80 patients with metastatic PNETs. In this study, somatic alterations were identified in 95% of the tested tumor samples, with the most commonly altered genes being MEN1 , DAXX , ATRX , and TSC2 . In this study, sequencing of pre- and post-treatment samples was also conducted, revealing progression in tumor grade as well as clonal evolution in the tumors. Germline analysis was also performed, with alterations identified in high-penetrance autosomal dominant cancer susceptibility genes ( MEN1 , TSC2 , and VHL ).

Of note, poorly differentiated pancreatic neuroendocrine carcinomas (PNECs) are clinically and genetically distinct from PNETs. The most commonly mutated genes in PNECs are the tumor suppressors p53 (95%) and Rb (74%). ^,

Pathology and staging

PNETs are generally well-circumscribed, solitary masses that can occur anywhere in the pancreas. The majority of PNETs are well differentiated. All PNETs have the potential to grow and eventually metastasize, and because of this, these tumors are considered malignant. Because the likelihood of metastatic spread is very low in subsets of patients with PNETs, the term “benign” has been used as a classification variable. Most classification schemes have considered PNET to be malignant if it invades locoregionally; has metastasized distantly or to regional lymph nodes; is greater than 2 cm in size; displays vascular, lymphatic, or perineural invasion; or has a proliferative index greater than 2% ^, (see Chapter 59 ).

PNETs are classified according to the 2017 World Health Organization (WHO) classification of pancreatic neuroendocrine neoplasms (PNENs). The pathologic classification by WHO 2017 criteria remains the most significant prognostic tool for the clinician because it offers information to predict tumor behavior and guide the selection of treatment.

The 2017 WHO classification stratifies PNENs by differentiation (well or poorly differentiated) and grade (grade 1, low; grade 2, intermediate; grade 3, high), with grade classified by proliferative index measured by Ki-67 and/or mitotic count. The mitotic index is expressed as the number of mitotic figures per 10 high-powered microscopic fields (HPFs), and it is recommended that 40 to 50 HPFs be examined. Ki-67 labeling tags neoplastic cells with an antibody and then reports the percentage of cells that stain positively ( Table 65.1 ). Well-differentiated NENs are defined as tumors (NETs), whereas poorly differentiated NENs are defined as carcinomas (NECs). The 2017 classification recognizes the heterogeneity of grade 3 pancreatic NENs, differentiating well-differentiated NETs and poorly differentiated NECs within the grade 3 category as distinct subtypes. Changes in the WHO classification for pancreatic NENs from 2010 to 2017 evolved through an understanding of distinct treatment responses and clinical outcomes for grade 3 PNETs in comparison to PNECs (see Chapter 58 ).

The staging system most commonly used in the United States for classifying PNETs is the 2017 American Joint Committee on Cancer tumor-node-metastasis system. Stage I indicates localized tumors, stages II and III more advanced local or regional disease, and stage IV distant metastases. The 5-year overall survival (OS) rates (nonfunctional and functional tumors combined) derived from analysis of the Surveillance Epidemiology and End Results (SEER) database are 62% for patients with localized tumors, 54% for those with regionally advanced disease, and 20% for patients with distant metastases.

Prognosis

Despite being classified as well differentiated, the majority of PNETs have pathologic features that increase the likelihood of future recurrence or have metastatic disease at the time of diagnosis. Low- and intermediate-grade (G1 and G2, respectively) PNETs have significantly better 5-year OS (75% and 63%, respectively) than do G3 tumors (7%), and functional tumors are associated with better survival than nonfunctional PNETs because they are more often identified at an earlier stage (68% vs. 60% 5-year OS). Approximately 60% of PNET cases have distant metastases at presentation, which is associated with decreased survival compared with those with local or locoregional disease. In addition to grade and the presence of distant metastases, age at diagnosis can also help stratify patients into prognostic categories because an older age at diagnosis correlates with impaired survival (<55 years, 67.8% 5-year OS vs. >75 years, 40.8% 5-year OS).

Familial syndromes

PNETs are associated with four familial diseases: MEN1, VHL, NF1, and TS. MEN1 is the most common of these syndromes, and approximately 5% to 7% of patients with PNETs will have MEN1. MEN1 is inherited in an autosomal dominant fashion and characterized by the development of parathyroid adenomas that will cause hyperparathyroidism in 90% of patients, multiple functional or nonfunctional PNETs in 75%, and pituitary adenomas in 40%. Adrenocortical tumors (both functional and nonfunctional), thymic tumors, and bronchial NETs are also seen in some patients. Genetic testing for MEN1 should be performed in all first-degree relatives (including children younger than 5 years) of affected patients and those who have had a germline mutation identified in the MEN1 gene. Approximately 30% to 50% of patients will present with metastases, complications of which are the most common cause of death from MEN1. ^, The surgical management of these tumors is complex and discussed in greater detail later (see Chapters 66 and 67 ).

VHL is an autosomal dominant syndrome caused by inactivation of the VHL gene, which is thought to play a role in angiogenesis. VHL predisposes patients to several cancers: renal cell carcinoma, pheochromocytoma, cerebellar and spinal hemangioblastoma, retinal angioma, endolymphatic sac neoplasms, epididymal cystadenoma, and cystic and solid pancreatic neoplasms. Between 10% and 15% of VHL patients will develop PNETs, although the most common pancreatic manifestation of this syndrome is serous cystadenoma. ^,

PNETs may also develop in TS and NF1. The tuberous sclerosis complex 1/2 (TSC1/2) inhibits mTOR, and a defect in the TSC2 gene leads to development of TS. NF1 , the gene responsible for NF1, regulates the activity of TSC2 . Loss of NF1 leads to constitutive mTOR activation. In TS, hamartomas may develop in the brain, eyes, heart, lungs, skin, kidneys, and pancreas. In NF1, the primary manifestation is the development of benign neurofibromas in multiple locations of the peripheral nervous system. Patients are also at risk for pheochromocytomas and sarcomas. In both TS and NF1, multiple PNETs may develop in the pancreas and duodenum. ^,

Functional tumors: Clinical features

PNETs are clinically classified into two categories: functional and nonfunctional. Functional PNETs produce clinical syndromes because of the hypersecretion of biologically active peptides. Functional PNETs tend to have better 5-year OS compared with nonfunctional PNETs. This is likely because they are detected earlier than nonfunctional PNETs because of the presence of symptoms.

Gastrinoma

Gastrinomas secrete gastrin, causing Zollinger-Ellison syndrome. This syndrome is named for Zollinger and his colleagues who, in 1955, published a case series detailing the clinical courses of two patients with gastric acid hypersecretion, severe peptic ulceration, and pancreatic tumors. The extraordinarily high levels of gastrin secreted by these tumors are the cause of the recurrent peptic ulcers, diarrhea, and reflux esophagitis experienced by most patients and cause the thickened mucosal folds in the stomach that are a hallmark of the disease. ^, These functional PNETs may be sporadic (67%) or familial (33%) and tend to be solitary tumors unless seen in the context of MEN1, in which case they are small, multiple, and most likely found in the duodenum (>85%). Regardless of their etiology, they are generally found within the gastrinoma triangle ( Fig. 65.1 ), which was described in 1984 to aid surgeons in finding these frequently diminutive tumors. The majority of gastrinomas are considered malignant (60%) and have spread to regional lymph nodes by the time they are diagnosed. Liver metastases are often associated with gastrinomas that arise in the pancreas. Laboratory diagnosis of the disease requires demonstration of hypergastrinemia and abnormal gastric acid secretion. This can be done by obtaining a fasting serum gastrin and a gastric pH. If the gastrin level is 10 times normal and the gastric pH is less than 2, the diagnosis is confirmed. If results are equivocal, a secretin or glucagon stimulation test can be performed because gastrinomas frequently express both receptors and respond by secreting abnormally large amounts of gastrin to the injected reagent. ^,