N o n f u n c t i o n a l P a n c re a t i c N e u ro e n d o c r i n e Tu m o r s Jennifer H. Kuo,
MD
a
, James A. Lee,
MD
b,
*, John A. Chabot,
MD
a
KEYWORDS Pancreas Neuroendocrine Nonfunctional Neuroendocrine liver metastases PanNET KEY POINTS Pancreatic neuroendocrine tumors are rare, heterogeneous tumors that compose 3% of all pancreatic neoplasms and 7% of all neuroendocrine tumors. The incidence of pancreatic neuroendocrine tumors has been increasing over the past 20 years because of the increased diagnosis of pancreatic incidentalomas. Ninety percent of pancreatic neuroendocrine tumors are nonfunctional tumors that are often malignant and present with symptoms of mass effect or metastatic disease. Formal surgical resection is the treatment of choice for most locoregional disease; however, surgical decision making must include many variables. Hepatic metastasis is common, and resection is recommended in the absence of extrahepatic disease. Interventional liver-directed therapies and targeted systemic therapies offer promising alternatives for patients with advanced disease, improving morbidity and increasing progression-free survival.
INTRODUCTION
Neuroendocrine tumors (NETs) are a group of rare, diverse neoplasms, which can be found throughout the body. They are most commonly located in the gastrointestinal tract and lung but are also found in the pancreas.1 Historically known as islet cell tumors, they are now classified as pancreatic NETs (PanNETs) by the World Health Organization (WHO). When compared with adenocarcinomas, PanNETs account for a relatively small percentage of pancreatic neoplasms,2,3 but their incidence has been increasing over the past 20 years. Based on the Surveillance, Epidemiology, and End Results (SEER) database, the incidence of NETs in the United States increased
a Division of GI/Endocrine Surgery, Columbia University, 161 Fort Washington Avenue, 8th Floor, New York, NY 10032, USA; b COACH Education, Endocrine Surgery, Adrenal Center, New York Thyroid/Parathyroid Center, Simulation Center, Columbia University, 161 Fort Washington Avenue, 8th Floor, New York, NY 10032, USA * Corresponding author. E-mail address: [email protected]
Surg Clin N Am 94 (2014) 689–708 http://dx.doi.org/10.1016/j.suc.2014.02.010 surgical.theclinics.com 0039-6109/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
690
Kuo et al
nearly 5-fold over the past 3 decades and was 5.25 per 100,000 in 2004.4 PanNETs account for 7% of all NETs5 and have an incidence of 0.43 per 100,000 people in 2007,5 a greater than 2-fold increase in the incidence of PanNETs since the 1980s. The increased frequency of abdominal imaging, specifically computed tomography (CT) and ultrasound, has increased the incidence of abnormal pancreatic findings detected in asymptomatic patients. Of these patients, 17% will ultimately undergo pancreatectomy.6 This increase in pancreatic incidentalomas may reflect a historical underestimation of the prevalence of this disease; autopsy studies suggest that the prevalence of PanNETs may be higher than we expect, with prevalence rates of 3% to 10%.7–9 RELEVANT ANATOMY/PATHOPHYSIOLOGY
Traditionally, PanNETs have been thought to arise from the islets of Langerhans that perform the endocrine function of the pancreas. More recent investigation, however, has demonstrated that these neoplasms originate from pluripotent cells in the pancreatic ductal/acinar system.10 All PanNETs express neuroendocrine markers, such as synaptophysin, neuron-specific enolase, and chromogranin A (CgA) (present in 88%–100% of patients with PanNETs). A multitude of cellular and molecular alterations have been implicated in the pathogenesis of PanNETs, involving at least 14 different types of cells and genetic alterations in the MEN-1 gene, the p16/MTS1 tumor-suppressor gene, the DPC4/Smad 4 gene, amplification of the Her-2/neu proto-oncogene, and alterations in transcription factors Hox C6, growth factors, and their receptor expressions.11 Several of these genetic alterations have been shown to correlate with tumor aggressiveness and may have prognostic significance.12 This molecular heterogeneity translates to heterogeneity in the clinical presentation, including both the multiple syndromes of overproduction and hypersecretion of hormones that have traditionally characterized these tumors as well as hormonally silent tumors. Thus, PanNETs are often classified as functional or nonfunctional based on the presence or absence of a particular clinical syndrome associated with hormone hypersecretion. According to the SEER database, from 1973 to 2000, most PanNETs diagnosed were nonfunctional tumors (90.8%); the remaining 9% included malignant functional tumors, such as gastrinomas (4.2%), insulinomas (2.5%), glucagonomas (1.6%), and VIPomas (0.9%).13,14 In addition to variability in the production of pancreatic endocrine hormones, PanNETs exhibit a broad range of growth rates, malignant potential, and overall prognosis. Although commonly perceived to be indolent tumors because they have a far better prognosis than pancreatic adenocarcinoma, most patients with PanNETs (60%–70%) present with metastatic disease.4,13,14 Even when they are resectable, many patients ultimately succumb to the disease. Following surgical resection of PanNETs, the 5-year survival for PanNETs other than insulinomas is roughly 65%, with a 10-year survival of 45%.14 In 2000, the WHO introduced a classification system based on clinical and histopathologic features that divides PanNETs into well-differentiated endocrine tumors with either benign or uncertain behavior, well-differentiated endocrine carcinomas, or poorly differentiated endocrine carcinomas.15 More recent classification systems have acknowledged the increasing importance of a proliferative index, specifically expression of the nuclear antigen Ki-67, and evidence of its prognostic value for PanNET.15–17 In 2010, the WHO revised the classification of PanNETs to reflect a proliferation-based grading system in conjunction with the traditional histopathologic diagnostic criteria (Table 1). They delineated a 3-tier grading system of PanNETs designating tumors as well-differentiated NETs versus poorly differentiated
Nonfunctional Pancreatic Neuroendocrine Tumors
Table 1 WHO classification of PanNETs Grade
Ki-67 Index (%)
Mitotic Count/10 HPF
G1
2
20
>20
TNM
Size (cm)
Muscularis Propria Invasion
T1a
2
1
In the World Health Organization (WHO) 2010, the higher grade is assumed if the Ki-67 index and mitotic count differ; in the WHO 2010 TNM, the tumor is classified as T2 if it is larger than 2 cm in diameter or if it invades the muscularis propria. T3 and T4 tumors are locally aggressive tumors (data not shown in the table). Abbreviation: HPF, high-power field. Data from Bosman F, Carneiro F, Hruban R, editors. WHO classification of tumors of the digestive system. Lyon (France): IARC Press; 2010.
neuroendocrine carcinomas. The well-differentiated NETs were further divided into grade 1 (Ki-67 20). Mitotic rate or Ki-67 should be assessed on all PanNETs. When both mitotic rate and Ki-67 are obtained, the higher grade is assigned. If the biopsy specimen is inadequate, a repeat biopsy is recommended.18 The European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC) describe alternative classification systems for PanNETs. The ENETS’ classification19 for PanNETs combines a staging TNM classification including the tumor diameter along with a grading system based on the mitotic rate and Ki-67.20 The AJCC’s TNM classification is based on a staging system for exocrine pancreatic adenocarcinomas, differentiating tumors based on the extent of disease rather than the tumor grade to determine tumor resectability.20 Although both systems emphasize different tumor characteristics, both classification systems have been demonstrated to be prognostic for relapse-free survival.20 It is important to note that histopathology is not always predictive of malignancy, and the only true measures of whether a PanNET is benign or malignant include evidence of local invasion, metastases, and/or recurrent disease. CLINICAL PRESENTATION
Most PanNETs are sporadic and tend to affect older individuals. Men have a slightly increased risk of developing PanNETs than women (55.2% vs 44.8%), and there is a Caucasian predominance in the United States (84.1% Caucasian vs 15.9% other background).13 Functional tumors present with symptoms that result from the specific hormone being elaborated. The most common functional PanNETs are insulinomas composing 30% to 45% of functioning PanNETs2,21 and gastrinomas composing 16% to 30%.21 Glucagonoma, VIPomas, and somatostatinomas are rarer PanNETs, and other rare functional PanNETs also exist.22 The presentation of these tumors is summarized in Table 2 but is not discussed in further detail in this article. Patients with nonfunctional tumors typically present with symptoms related to local mass effect or metastatic disease, indicating a more advanced stage of disease.9
691
692
Kuo et al
Table 2 Summary of functional NETs Tumor Type
Numbera
Secretory Hormone
Clinical Features
Laboratory Tests
Symptomatic Treatment
Insulinoma
40%–60%
Insulin
Hypoglycemia; symptoms of catecholamine excess; 90% benign
Insulin level, C-reactive protein; 72-h inpatient fasting with monitoring of glucose and insulin levels
Dietary modifications; octreotide; diazoxide
Gastrinoma
20%–50%
Gastrin
Peptic ulcer disease; GERD; secretory diarrhea; most common PanNET in MEN-1; 60%–90% malignant
Fasting serum gastrin; gastric pH analysis, gastrin provocation testing (calcium or secretin challenge)
Proton pump inhibitor; octreotide
Glucagonoma
Rare
Glucagon
Glucose intolerance; migratory necrolytic erythema; weight loss; anemia; 90% malignant
Serum glucagon
Octreotide; insulin; zinc supplement (rash); TPN (malnutrition)
Somatostatinoma
Rare
Somatostatin
Diabetes; gallstones; secretory diarrhea
Clinical and pathologic diagnoses; increased somatostatinlike immunoreactivity in resected tumor
Octreotide
VIPoma
Rare
Vasoactive intestinal peptide
Choleralike, secretory diarrhea; hypokalemia; hypochlorhydria
Serum VIP
Octreotide
Abbreviations: GERD, gastroesophageal reflux disease; MEN-1, multiple endocrine neoplasia type 1; TPN, total parenteral nutrition; VIP, vasoactive intestinal polypeptide. a Percentage among PanNETs.
Nonfunctional Pancreatic Neuroendocrine Tumors
Nonfunctioning tumors either do not produce any hormone, produce very small amounts of hormones that are insufficient to produce symptoms, or produce hormones that do not generate specific symptoms (pancreatic polypeptide, human chorionic gonadotropin subunits, calcitonin, or neurotensin).23,24 Most nonfunctional tumors occur in the head of the pancreas and often produce symptoms of mass effect that mimic those of pancreatic adenocarcinoma, including jaundice, abdominal pain, weight loss, abdominal mass, nausea and vomiting, backache, and pancreatitis.22,25,26 As previously mentioned, the number of pancreatic tumors discovered incidentally before any onset of symptoms is dramatically increasing because of the widespread use of abdominal imaging.6,9,23 Bruzoni and colleagues27 found that 19% of these pancreatic incidentalomas were NETs on the final pathology. Although most PanNETs occur sporadically, nearly 10% are associated with predisposing genetic syndromes. These hereditary syndromes include multiple endocrine neoplasia type 1 (MEN-1 syndrome), von Hippel-Lindau disease (VHL), von Recklinghausen disease or neurofibromatosis type 1 (NF-1), and tuberous sclerosis complex (TSC).2,9,14,21 These patients are generally diagnosed at a younger age, have multiple synchronous lesions throughout the pancreas, and have a family history of endocrine disorders or their associated cancers.9,21 The most recognized of these hereditary syndromes is MEN-1.2,9,14,21 Most patients with MEN-1 (80%–100%) develop nonfunctioning PanNETs, 50% to 60% develop gastrinomas, 20% insulinomas, and 3% to 5% VIPomas or glucagonomas.2,9,14,21 Nonfunctional PanNETs, cystic pancreatic lesions, and mixed serous-NETs can be seen in 20% of patients with VHL.2,14,21 In contrast to MEN-1 and VHL, PanNETs are relatively uncommon in patients with NF-1 and TSC (3 cm).
Fig. 1. PanNETs appear as well-circumscribed, hypervascular lesions on CT imaging. CT has a high sensitivity for detecting PanNETs greater than 2 cm in size and offers excellent anatomic and spatial detail. Arrow points to neuroendocrine tumor.
Nonfunctional Pancreatic Neuroendocrine Tumors
The sensitivity of contrast-enhanced CT approaches 100% (imaging study of choice). Dual-phase (arterial and portal) imaging detects pancreatic neoplasms and delineates local vascular anatomy. Oral contrast allows optimum visualization of the duodenum, improving the detection of duodenal gastrinomas. MRI
PanNETs are typically characterized by low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. (Tumors
MD
a
, James A. Lee,
MD
b,
*, John A. Chabot,
MD
a
KEYWORDS Pancreas Neuroendocrine Nonfunctional Neuroendocrine liver metastases PanNET KEY POINTS Pancreatic neuroendocrine tumors are rare, heterogeneous tumors that compose 3% of all pancreatic neoplasms and 7% of all neuroendocrine tumors. The incidence of pancreatic neuroendocrine tumors has been increasing over the past 20 years because of the increased diagnosis of pancreatic incidentalomas. Ninety percent of pancreatic neuroendocrine tumors are nonfunctional tumors that are often malignant and present with symptoms of mass effect or metastatic disease. Formal surgical resection is the treatment of choice for most locoregional disease; however, surgical decision making must include many variables. Hepatic metastasis is common, and resection is recommended in the absence of extrahepatic disease. Interventional liver-directed therapies and targeted systemic therapies offer promising alternatives for patients with advanced disease, improving morbidity and increasing progression-free survival.
INTRODUCTION
Neuroendocrine tumors (NETs) are a group of rare, diverse neoplasms, which can be found throughout the body. They are most commonly located in the gastrointestinal tract and lung but are also found in the pancreas.1 Historically known as islet cell tumors, they are now classified as pancreatic NETs (PanNETs) by the World Health Organization (WHO). When compared with adenocarcinomas, PanNETs account for a relatively small percentage of pancreatic neoplasms,2,3 but their incidence has been increasing over the past 20 years. Based on the Surveillance, Epidemiology, and End Results (SEER) database, the incidence of NETs in the United States increased
a Division of GI/Endocrine Surgery, Columbia University, 161 Fort Washington Avenue, 8th Floor, New York, NY 10032, USA; b COACH Education, Endocrine Surgery, Adrenal Center, New York Thyroid/Parathyroid Center, Simulation Center, Columbia University, 161 Fort Washington Avenue, 8th Floor, New York, NY 10032, USA * Corresponding author. E-mail address: [email protected]
Surg Clin N Am 94 (2014) 689–708 http://dx.doi.org/10.1016/j.suc.2014.02.010 surgical.theclinics.com 0039-6109/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
690
Kuo et al
nearly 5-fold over the past 3 decades and was 5.25 per 100,000 in 2004.4 PanNETs account for 7% of all NETs5 and have an incidence of 0.43 per 100,000 people in 2007,5 a greater than 2-fold increase in the incidence of PanNETs since the 1980s. The increased frequency of abdominal imaging, specifically computed tomography (CT) and ultrasound, has increased the incidence of abnormal pancreatic findings detected in asymptomatic patients. Of these patients, 17% will ultimately undergo pancreatectomy.6 This increase in pancreatic incidentalomas may reflect a historical underestimation of the prevalence of this disease; autopsy studies suggest that the prevalence of PanNETs may be higher than we expect, with prevalence rates of 3% to 10%.7–9 RELEVANT ANATOMY/PATHOPHYSIOLOGY
Traditionally, PanNETs have been thought to arise from the islets of Langerhans that perform the endocrine function of the pancreas. More recent investigation, however, has demonstrated that these neoplasms originate from pluripotent cells in the pancreatic ductal/acinar system.10 All PanNETs express neuroendocrine markers, such as synaptophysin, neuron-specific enolase, and chromogranin A (CgA) (present in 88%–100% of patients with PanNETs). A multitude of cellular and molecular alterations have been implicated in the pathogenesis of PanNETs, involving at least 14 different types of cells and genetic alterations in the MEN-1 gene, the p16/MTS1 tumor-suppressor gene, the DPC4/Smad 4 gene, amplification of the Her-2/neu proto-oncogene, and alterations in transcription factors Hox C6, growth factors, and their receptor expressions.11 Several of these genetic alterations have been shown to correlate with tumor aggressiveness and may have prognostic significance.12 This molecular heterogeneity translates to heterogeneity in the clinical presentation, including both the multiple syndromes of overproduction and hypersecretion of hormones that have traditionally characterized these tumors as well as hormonally silent tumors. Thus, PanNETs are often classified as functional or nonfunctional based on the presence or absence of a particular clinical syndrome associated with hormone hypersecretion. According to the SEER database, from 1973 to 2000, most PanNETs diagnosed were nonfunctional tumors (90.8%); the remaining 9% included malignant functional tumors, such as gastrinomas (4.2%), insulinomas (2.5%), glucagonomas (1.6%), and VIPomas (0.9%).13,14 In addition to variability in the production of pancreatic endocrine hormones, PanNETs exhibit a broad range of growth rates, malignant potential, and overall prognosis. Although commonly perceived to be indolent tumors because they have a far better prognosis than pancreatic adenocarcinoma, most patients with PanNETs (60%–70%) present with metastatic disease.4,13,14 Even when they are resectable, many patients ultimately succumb to the disease. Following surgical resection of PanNETs, the 5-year survival for PanNETs other than insulinomas is roughly 65%, with a 10-year survival of 45%.14 In 2000, the WHO introduced a classification system based on clinical and histopathologic features that divides PanNETs into well-differentiated endocrine tumors with either benign or uncertain behavior, well-differentiated endocrine carcinomas, or poorly differentiated endocrine carcinomas.15 More recent classification systems have acknowledged the increasing importance of a proliferative index, specifically expression of the nuclear antigen Ki-67, and evidence of its prognostic value for PanNET.15–17 In 2010, the WHO revised the classification of PanNETs to reflect a proliferation-based grading system in conjunction with the traditional histopathologic diagnostic criteria (Table 1). They delineated a 3-tier grading system of PanNETs designating tumors as well-differentiated NETs versus poorly differentiated
Nonfunctional Pancreatic Neuroendocrine Tumors
Table 1 WHO classification of PanNETs Grade
Ki-67 Index (%)
Mitotic Count/10 HPF
G1
2
20
>20
TNM
Size (cm)
Muscularis Propria Invasion
T1a
2
1
In the World Health Organization (WHO) 2010, the higher grade is assumed if the Ki-67 index and mitotic count differ; in the WHO 2010 TNM, the tumor is classified as T2 if it is larger than 2 cm in diameter or if it invades the muscularis propria. T3 and T4 tumors are locally aggressive tumors (data not shown in the table). Abbreviation: HPF, high-power field. Data from Bosman F, Carneiro F, Hruban R, editors. WHO classification of tumors of the digestive system. Lyon (France): IARC Press; 2010.
neuroendocrine carcinomas. The well-differentiated NETs were further divided into grade 1 (Ki-67 20). Mitotic rate or Ki-67 should be assessed on all PanNETs. When both mitotic rate and Ki-67 are obtained, the higher grade is assigned. If the biopsy specimen is inadequate, a repeat biopsy is recommended.18 The European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC) describe alternative classification systems for PanNETs. The ENETS’ classification19 for PanNETs combines a staging TNM classification including the tumor diameter along with a grading system based on the mitotic rate and Ki-67.20 The AJCC’s TNM classification is based on a staging system for exocrine pancreatic adenocarcinomas, differentiating tumors based on the extent of disease rather than the tumor grade to determine tumor resectability.20 Although both systems emphasize different tumor characteristics, both classification systems have been demonstrated to be prognostic for relapse-free survival.20 It is important to note that histopathology is not always predictive of malignancy, and the only true measures of whether a PanNET is benign or malignant include evidence of local invasion, metastases, and/or recurrent disease. CLINICAL PRESENTATION
Most PanNETs are sporadic and tend to affect older individuals. Men have a slightly increased risk of developing PanNETs than women (55.2% vs 44.8%), and there is a Caucasian predominance in the United States (84.1% Caucasian vs 15.9% other background).13 Functional tumors present with symptoms that result from the specific hormone being elaborated. The most common functional PanNETs are insulinomas composing 30% to 45% of functioning PanNETs2,21 and gastrinomas composing 16% to 30%.21 Glucagonoma, VIPomas, and somatostatinomas are rarer PanNETs, and other rare functional PanNETs also exist.22 The presentation of these tumors is summarized in Table 2 but is not discussed in further detail in this article. Patients with nonfunctional tumors typically present with symptoms related to local mass effect or metastatic disease, indicating a more advanced stage of disease.9
691
692
Kuo et al
Table 2 Summary of functional NETs Tumor Type
Numbera
Secretory Hormone
Clinical Features
Laboratory Tests
Symptomatic Treatment
Insulinoma
40%–60%
Insulin
Hypoglycemia; symptoms of catecholamine excess; 90% benign
Insulin level, C-reactive protein; 72-h inpatient fasting with monitoring of glucose and insulin levels
Dietary modifications; octreotide; diazoxide
Gastrinoma
20%–50%
Gastrin
Peptic ulcer disease; GERD; secretory diarrhea; most common PanNET in MEN-1; 60%–90% malignant
Fasting serum gastrin; gastric pH analysis, gastrin provocation testing (calcium or secretin challenge)
Proton pump inhibitor; octreotide
Glucagonoma
Rare
Glucagon
Glucose intolerance; migratory necrolytic erythema; weight loss; anemia; 90% malignant
Serum glucagon
Octreotide; insulin; zinc supplement (rash); TPN (malnutrition)
Somatostatinoma
Rare
Somatostatin
Diabetes; gallstones; secretory diarrhea
Clinical and pathologic diagnoses; increased somatostatinlike immunoreactivity in resected tumor
Octreotide
VIPoma
Rare
Vasoactive intestinal peptide
Choleralike, secretory diarrhea; hypokalemia; hypochlorhydria
Serum VIP
Octreotide
Abbreviations: GERD, gastroesophageal reflux disease; MEN-1, multiple endocrine neoplasia type 1; TPN, total parenteral nutrition; VIP, vasoactive intestinal polypeptide. a Percentage among PanNETs.
Nonfunctional Pancreatic Neuroendocrine Tumors
Nonfunctioning tumors either do not produce any hormone, produce very small amounts of hormones that are insufficient to produce symptoms, or produce hormones that do not generate specific symptoms (pancreatic polypeptide, human chorionic gonadotropin subunits, calcitonin, or neurotensin).23,24 Most nonfunctional tumors occur in the head of the pancreas and often produce symptoms of mass effect that mimic those of pancreatic adenocarcinoma, including jaundice, abdominal pain, weight loss, abdominal mass, nausea and vomiting, backache, and pancreatitis.22,25,26 As previously mentioned, the number of pancreatic tumors discovered incidentally before any onset of symptoms is dramatically increasing because of the widespread use of abdominal imaging.6,9,23 Bruzoni and colleagues27 found that 19% of these pancreatic incidentalomas were NETs on the final pathology. Although most PanNETs occur sporadically, nearly 10% are associated with predisposing genetic syndromes. These hereditary syndromes include multiple endocrine neoplasia type 1 (MEN-1 syndrome), von Hippel-Lindau disease (VHL), von Recklinghausen disease or neurofibromatosis type 1 (NF-1), and tuberous sclerosis complex (TSC).2,9,14,21 These patients are generally diagnosed at a younger age, have multiple synchronous lesions throughout the pancreas, and have a family history of endocrine disorders or their associated cancers.9,21 The most recognized of these hereditary syndromes is MEN-1.2,9,14,21 Most patients with MEN-1 (80%–100%) develop nonfunctioning PanNETs, 50% to 60% develop gastrinomas, 20% insulinomas, and 3% to 5% VIPomas or glucagonomas.2,9,14,21 Nonfunctional PanNETs, cystic pancreatic lesions, and mixed serous-NETs can be seen in 20% of patients with VHL.2,14,21 In contrast to MEN-1 and VHL, PanNETs are relatively uncommon in patients with NF-1 and TSC (3 cm).
Fig. 1. PanNETs appear as well-circumscribed, hypervascular lesions on CT imaging. CT has a high sensitivity for detecting PanNETs greater than 2 cm in size and offers excellent anatomic and spatial detail. Arrow points to neuroendocrine tumor.
Nonfunctional Pancreatic Neuroendocrine Tumors
The sensitivity of contrast-enhanced CT approaches 100% (imaging study of choice). Dual-phase (arterial and portal) imaging detects pancreatic neoplasms and delineates local vascular anatomy. Oral contrast allows optimum visualization of the duodenum, improving the detection of duodenal gastrinomas. MRI
PanNETs are typically characterized by low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. (Tumors
