Available online at www.sciencedirect.com EJSO 34 (2008) 324e332 www.ejso.com Review Pancreatic neuroendocrine tumours H.L. O’Grady, K.C. Conlon* Centre for Pancreaticobiliary Diseases, AMNCH, Tallaght, Dublin 24, Ireland Accepted 20 July 2007 Available online 29 October 2007 Abstract Pancreatic neuroendocrine tumours (PET) are rare neoplasms of the pancreas accounting for less than 5% of all primary pancreatic malignancies. Included in this group are insulinomas, gastrinomas, glucagonoma and somatostatinomas. Collectively these neoplasms are classified as functional PETs. Where a PET is not associated with a clinical syndrome due to hormone oversecretion, it is referred to as a non-functioning PET. Non-functioning PETs are pancreatic tumours with endocrine differentiation but lack a clinical syndrome of hormone hypersecretion. The incidence of these tumours varied between 15 and 53%. Presentation is related to the mass effect of the tumour with symptoms often non-specific. Treatment is surgical excision with chemotherapy and hormonal therapy is controversial. For functioning PETs, surgery remains the optimal therapy, however, long-term survival can be expected even in the presence of metastases. With advances in medical management, radiolabelled somatostatin therapy, hepatic arterial chemoembolisation and radiofrequency ablation, symptoms may be controlled to optimize quality of life. Ó 2007 Published by Elsevier Ltd. Keywords: Neuroendocrine; Pancreas; Insulinoma; Gastrinoma Introduction Pancreatic neuroendocrine tumours (PET) are rare neoplasms of the pancreas accounting for less than 5% of all primary pancreatic malignancies.1 It is important to distinguish PET’s from the more common adenocarcinoma because the prognosis for PET’s is superior, even in the face of metastatic disease.2 During embryogenesis pancreatic islet cells develop as cellular buds from intraobular ductless. This process is generally complete by birth. As islet cells demonstrate hormone coexpression in fetal life, it is thought that neuroendocrine tumours originate from multipotent cells in the ductal epithelium that retain their ability to differentiate toward the cell line found in the tumour.3 Originally described by Nicholls in 1902 as tumours originating from pancreatic islet cell lineage,4 these tumours are commonly associated with the clinical syndrome related to the * Corresponding author. Tel.: þ353 1 896 3719; fax: þ353 1 896 3788. E-mail address: profsurg@tcd.ie (K.C. Conlon). 0748-7983/$ - see front matter Ó 2007 Published by Elsevier Ltd. doi:10.1016/j.ejso.2007.07.209 hormone secreted by the tumour. Included in this group are insulinomas, gastrinomas, glucagonoma and somatostatinomas.5 Collectively these neoplasms are classified as functional PET’s. Where a PET is not associated with a clinical syndrome due to hormone oversecretion it is referred to as a non-functioning PET. Clinically these two groups present differently- one due to the effects of hormone overproduction and nonfunctional lesions generally due to mass effect or metastases. Although these tumours tend to be less aggressive than their adenocarcinoma counterpart they frequently metastasize to the liver.6 At the time of diagnoses, excluding insulinoma, 50e60% of PET’s have metastasized.7,8 Non-functioning PET’s are pancreatic tumours with endocrine differentiation but lack a clinical syndrome of hormone hypersecretion. Although these tumours are hormonally ‘‘silent’’ they may produce a precursor hormone that is functionally inert, or at an amount that is too small to cause symptoms. Non-functioning tumours are slow growing and occur most commonly in the head of the pancreas.9 The incidence of non-functional tumours has varied between 15 and 53%.10,11 This wide variation in incidence H.L. O’Grady, K.C. Conlon / EJSO 34 (2008) 324e332 325 may be explained by technical advances in imaging modalities that has enabled clinically silent intra-abdominal lesions to be identified. Presentation is related to the mass effect of the tumour with symptoms resembling those of pancreatic adenocarcinoma- jaundice, abdominal pain, weight loss or the appearance of an abdominal mass are the most frequent symptoms. Patients with non-functioning PET’s can present with advanced metastatic disease and relatively few symptoms. The prognosis of patients diagnosed with a PET is difficult to predict as the natural history of these tumours is largely unknown. Studies of patients with gastrinomas, where there is treatment for the symptoms of hypersecretion and so long-term follow-up is possible, indicate that up to 40% of PET’s demonstrate an indolent growth pattern.12,13 Indeed, tumour related deaths occur in PET’s that demonstrate an aggressive growth pattern e aggressive treatment should therefore be considered in these patients. One of the difficulties that exists is the definition of malignant and benign disease e PET are classified as malignant when lymph nodes are involved, distant metastases are identified or there is invasion into adjacent structures. Tumours therefore classified as benign may merely have had their natural history interrupted by surgical resection. In a study by Hochwald et al. of 136 cases of PET, the mitotic rate and necrosis shown to be of prognostic significance.14 No survival difference has been shown between functional and non-function PET’s. Due to the lack of symptoms, non-functional tumours tend to present later with much larger lesions than their functional counterpart (1.9 cm vs. 4 cm).15 The commonest genetic syndrome associated with PET is the multiple endocrine neoplasia type one syndrome (MEN 1), characterized by pancreatic, pituitary and parathyroid malignancies. Less frequently adrenal and carcinoid neoplasms may also be associated with this syndrome. Inherited patterns are consistent with autosomal dominant distribution and the gene has been traced to chromosome 11q13. This MEN 1 gene is a tumour suppressor gene and in genotypic studies of families with MEN 1 is 99% accurate in detecting MEN abnormalities.10 Multiple endocrine neoplasia is most commonly associated with gastrinomas and seen in 20e30% of patients with ZollingerEllison syndrome (ZES).16 It is important to diagnose MEN-1 in association with ZES as tumours tend to be multifocal, less aggressive and located submucosaly in the duodenum. Pancreatic neuroendocrine tumours also occur in von Hippel Lindau syndrome and von Recklinghausen disease. Figure 1. Multi detector CT image demonstrating a neuroendocrine tumour in the head of the pancreas. Figure 2. Venous phase image outlining the portal and superior mesenteric veins (indicated by blue arrows). Localization/imaging Transabdominal ultrasound is a cheap and widely available imaging modality. It has a sensitivity in detecting PET’s ranging from 9 to 64%.17,18 The use of endoscopic ultrasound has further improved the accuracy of preoperative ultrasound. Endoscopic ultrasound (EUS) allows high definition imaging of the walls of the stomach and duodenum and its adjacent structures, enabling lesions as small as 0.5 cm to be detected (Fig. 1).19 In addition, a tissue diagnosis may be made by fine needle aspiration cytology which is very useful in the case of non-functional PET’s enables. Endoscopic ultrasound is best at detecting lesions in the head of the pancreas and less so for more distal lesions.20e22 The sensitivity for detecting pancreatic gastrinomas has been shown to be 85%, but only 43% for duodenal gastrinomas.23 As the majority of gastrinomas are located in the duodenum, this is a significant limitation. Also approximately 50% of the duodenal gastrinomas localized with endoscopic ultrasound will be seen at endoscopy and not by ultrasound.24 Operator expertise is an important factor in the sensitivity of EUS.25 As the endoscope is difficult to maneuver and PET’s tend to be small, 326 H.L. O’Grady, K.C. Conlon / EJSO 34 (2008) 324e332 Figure 3. Arterial phase demonstrating the hepatic artery. unless in the hands of an experienced operator the test may be futile. Multi-detector Computerized Tomography is the investigation of choice and is infact the initial test performed due its widespread availability (Fig. 2). The generation of the scanner is important. Gouya et al. demonstrated that multidetector-CT was superior to single phase sequential CT (sensitivity 94% vs. 24%).26 Multidetector CT enables multiphasic thin slices to be acquired in a single breath hold. A dual phase image in both arterial and portal phases is used to detect pancreatic neoplasms and also to show peripancreatic vascular anatomy. Following a bolus of non-ionic contrast, thin slice images are obtained at 45 s and 70 s for arterial and portal phased respectively (Figs. 3 and 4).27 A negative oral contrast agent such as water allows optimum visualization of the duodenum, improving the detection of duodenal gastrinomas.28,29 In addition, Magnet Resonance Imaging (MRI) has been increasingly used in pancreas imaging. Pancreatic neuroendocrine tumours typically have a low signal density on T1-weighted images and high signal density on T2 weighted images. The use of gadolinium as a contrast agent is more sensitive for detecting vascular lesions than the standard iodinated contrast agents.30,31 As with most imaging modalities, size of the lesion predicts the sensitivity of pick-up. Tumours less than 1 cm were not detected by MRI with gadolinium and only 50% of tumours between 1 and 2 cm will be identified.32 Two studies unique to the localization of insulinomas and gastrinomas are percutaneous transhepatic portal venous sampling (PTPVS) and arterial stimulation with venous sampling (ASVS). These tests have been proposed as the most sensitive preoperative localisation investigation.33e35 Percutaneous-transhepatic portal venous sampling involves the placement of a catheter trans-hepatically in the portal vein and sequential manipulation into the splenic, superior mesenteric and portal vein for venous sampling. Intraarterial calcium is a potent stimulator of insulin production from islet b cells. A catheter advanced from the femoral artery and placed selectively in the splenic, superior mesenteric and gastroduodenal arteries with infusion of calcium gluconate followed by venous sampling from the hepatic vein. Generally the pancreatic body and tail are supplied by the splenic artery, the head by the gastroduodenal artery and the uncinate process by branches of the superior mesenteric artery. A two fold increase in hormone level confirms the diagnosis.36 Insulinomas will be accurately localized using this technique with a sensitivity of greater than 90%. Due to its invasive nature, it may be appropriate to use this technique where all non-invasive tests are negative, but an insulinoma is strongly suspected. Somatostatin receptor scintigraphy (SRS) also has a role in the preoperative localization of the primary disease as well as metastases.37,38 Many PET’s have an abundance of somatostain subtype 2 receptors. These are present in 100% of gastrinomas but only 62% of insulinomas.39 A somatostatin analogue 111In-DTPA-D-Phel 1 octreotide is administered and binds to all tissue expressing a significant concentration of somatostatin subtype 2 receptors. Scintigraphy is good for detecting hepatic and bone metastases from non-insulinoma PET’s,40 unfortunately it gives no information on tumour size or surgical resectability. Laparoscopic intraoperative ultrasound is a new technique that in a study by Grover et al. was successful in localizing insulinomas in 86% of cases and when combined with CT scanning localized the lesion in 93% of patients.41 This technique is not only beneficial in locating the primary tumour that may be small and multifocal when associated with MEN syndrome, but in also detecting occult metastases.42 Failure of this method may occur with nodular and cystic lesions of the pancreas which occurs with increasing age making localization more difficult.43 Insulinoma Figure 4. Endoscopic ultrasound image demonstrating hypoechoic tumour. Insulinomas are PET’s arising from the insulin producing islet b cells, and are the commonest type of PET. Although they have a malignant potential the majority of insulinomas are benign (90%). They are generally found within the pancreatic parenchyma (Figs. 5 and 6) equally distributed throughout the gland, with only 3% being found in ectopic locations. The duodenal mucosa is the H.L. O’Grady, K.C. Conlon / EJSO 34 (2008) 324e332 327 Table 1 Diagnostic criteria for insulinoma post fasting Plasma glucose Plasma insulin Plasma C-peptide Plasma proinsulin Plasma sulphonylurea Plasma b-hydroxybutyrate Change in glucose with 1 mg glucagons Figure 5. Benign insulinoma in the body of the pancreas resected following splenic preserving distal pancreatectomy. commonest location for ectopic insulinomas. Usually they are solitary lesions, however if multiple lesions are identified, MEN 1 syndrome should be considered. Presentation of insulinomas is with symptoms of hypoglycemia due to uncontrolled insulin productionconfusion, behavioral changes, blurred vision, fatigue, seizures, coma and even death. Whipples’ triad of hypoglycemic symptoms in the presence of low plasma glucose levels and resolution of symptoms following glucose administration suggest hyperinsulinemia. It should be noted however, that an insulinoma is an uncommon cause of hypoglycemia. The commonest cause of hypoglycemia is the administration of antidiabetic drugs-sulphonylureas and exogenous insulin.44 It is therefore mandatory to ensure that hyperinsulinemia is secondary to endogenous insulin production (Table 1). Commercially available insulin contains no C-peptide-if measurement of C-peptide is low then exogenous insulin administration must be suspected.45 Sulphonylureas produce glucose and C-peptide levels similar to those found with insulinomas, plasma levels of 2.5 mmol/L 6 munits/ml 0.2 nmol/L 0.5 nmol/L Negative <2.7 mmol/L 25 mg/dl at 30 min sulphonylureas should therefore be assessed in the diagnosis of insulinomas. Following admission to hospital a supervised fast is conducted with blood assessed every 6 h for glucose, insulin and C-peptide, or when symptoms occur. The following are diagnostic for insulinoma: blood glucose 2.5 mmol/l, insulin 6 munits/ml, C-peptide 0.2 nmol/l and a negative sulphonylurea screen. Nesidiobiosis is another uncommon cause of hypoglycemia as a result of diffuse islet cell hyperplasia. Once the biochemical diagnosis has been made, localization is important to plan treatment options. As insulinomas are equally distributed throughout the pancreas, a blind resection would fail to remove the tumour in 50% of cases and is therefore not recommended. If preoperative investigations fail to demonstrate a lesion that has been biochemically confirmed, intraoperative ultrasound improves localization.46 When intraoperative ultrasound is combined with surgeon palpation and full mobilization of the pancreas, >95% of insulinomas can be localized.47 When all modalities of localisation fail including intra-operative venous sampling, and given the low grade of malignancy (10%), so called ‘‘blind resection’’ should not be performed. Close follow up is recommended until the lesion is located. Once localized, surgical resection is the treatment of choice as it offers the best chance at a cure (Figs. 5 and 6). Procedures employed include enucleation, distal pancreatectomy and pancreaticoduodenectomy procedure. As the majority of these tumours are benign, enucleation of the lesion may be feasible when preoperative scans and intraoperative ultrasonography demonstrate that the tumour is separate from the pancreatic duct by 2e3 mm and surrounding vascular structures. It is also recommended that these tumours be managed in specialized centres.48 Surgical techniques can be performed open or laparoscopically. Although the conversion rate is 14%, this most likely represents the learning curve for this procedure.49 Malignant insulinomas invade locally and metastasise to regional lymph node and the liver. Outcome depends on the stage of the disease. Malignant insulinomas are generally solitary and larger than their benign counterparts4 cm or more on average.50 The presence or absence of liver metastases is a predictor of survival and also dictates treatment options.51 Gastrinoma Figure 6. Insulinoma resected from the body of the pancreas. Gastrinomas are the second commonest PET, occurring only half as often as insulinomas. They are most frequently diagnosed in the 5th and 6th decades of life 328 H.L. O’Grady, K.C. Conlon / EJSO 34 (2008) 324e332 with a slight female preponderance. At the time of diagnosis 50e60% of patients will have evidence of metastases.52 In 1955 Zollinger-Ellison described a syndrome in a patient with upper jejeunal ulceration, gastric acid hypersecretion and a tumour of the non-b cells of the pancreas. Gastrin has been identified as the causative agent. Patients typically present with symptoms of peptic ulcer disease in 90% of cases, and a small ulcer is found in 75% of patients in the 1st part of the duodenum. Diarrhoea occurs in approximately 40% of patients as a result of gastric acid hypersecretion. The excess acid within the intestine lowers intraluminal pH with resultant damage to the mucosal lining and malabsorption. The average time to diagnosis may be as long as 5 years.53 Following localisation techniques, described previously, 90% of gastrinomas54 will be located in a well defined area known as the ‘‘Gastrinoma Triangle’’ e junction of the pancreatic body and neck, the junction of the 2nd and 3rd portion of the duodenum and the junction of the cystic duct and common bile duct (Fig. 7). As many gastrinomas will have metastasized at the time of diagnosis, imaging modalities should be directed at the liver as well as the pancreas and duodenum. The symptoms of acid hypersecretion can be effectively controlled by proton pump inhibitors in virtually all patients with ZollingereEllison syndrome. Total gastrectomy and parietal cell vagotomy are therefore generally not currently indicated for acid control. The dose of proton pump inhibitor needed to control symptoms is generally higher than the usual peptic ulcer disease patient. In a study by Norton and colleagues, a mean of 80 mg of omeprazole was required to control acid symptoms.55 The long term effects of prolonged proton pump inhibitor therapy is however not fully known. The development of carcinoid tumours in the stomach is rare but has been reported in Figure 7. Gastrinoma triangle: junction of the pancreatic body and neck, the junction of the 2nd and 3rd portion of the duodenum and the junction of the cystic duct and common bile duct. patients with ZES. In these patients a surgical approach may be warranted. As adequate medical therapy now exists to control the symptoms of acid hypersecretion, debate now centers around the need for a surgical approach to the primary tumour. In our opinion, as surgical resection offers the only potential cure it should be considered in all patients with localized disease who are fit for surgical resection. Norton et al have reported a significant increased survival (98% fifteen year survival) following gastrinoma resection.56 It should also be noted however, the 15 year survival for unresected gastrinomas was 74%. The majority of non-MEN 1 associated gastrinomas are solitary and identifiable at laparotomy and are therefore ameniable to enucleation or resection if locally invasive. Following resection only 3% developed hepatic metastases after a 6-year follow-up period compared to 23% without resection.57 The long-term survival and low mortality and morbidity associated with surgical exploration58 support its routine use. The role of surgical exploration in gastrinomas associated with MEN 1 is more controversial. Following surgical exploration, only 16% of patients with MEN 1/ZES were disease free immediately after surgery, and only 6% were disease free at 5 years.59 A cure of Zollinger-Ellison syndrome in patients with MEN 1 rarely occurs. Glucagonoma Becker et al. was the first to identify a skin disorder associated with a pancreatic neoplasm in 1942.60 The classical presentation is with the ‘‘4D’s’’ of diabetes, dermatitis, Figure 8. Necrolytic migratory erythema. H.L. O’Grady, K.C. Conlon / EJSO 34 (2008) 324e332 deep vein thrombosis and depression. Glucagon has many important effects on glucose, fat and protein metabolism. It stimulates gluconeogenesis and inhibits glycolysis within the liver. In muscle it stimulates muscle breakdown and the flow of gluconeogenic amino acids alanine and glutamine from muscle to the liver. Thus in hyperglucagonemia, diabetes mellitus develops at the expense of tissue glycogen stores in muscle and fat. The pathognomic rash is known as necrolytic migratory erythema (Fig. 8) and may appear before other symptoms of hyperglucagonemia. It is the presenting feature in 70% of patients with glucagonoma.61 This characteristic rash consists of erythema with superficial areas of epidermal necrosis. This progresses to epidermal shedding, bullae formation and crusted erosions. Following treatment and normalization of glucagons levels, this rash generally resolves. At the time of presentation the tumours are generally quiet large (>4 cm) and up to 50% of patients with a glucagonoma will have evidence of distant disease62 most commonly the liver. As the lesions are relatively larger than other PET’s, localization within the gland is generally not an issue-the tail of the gland being the commonest location. Even in the presence of metastases, prolonged survival may be expected63 and treatment with somatostatin analogues may benefit symptoms.64 VIPoma Vasoactive intestinal peptide (VIP) acts on the intestinal lumen to stimulate the secretion of fluids and electrolytes into the intestine. This combines to result in a profuse watery diarrhea with loss of water, sodium, chloride and potassium from the body. This syndrome was initially noted in 195765 and further characterised by Verner and Morrisson, this syndrome now bears their name.66 The first step in the management of these patients is the correction of dehydration and electrolyte abnormalities. Octreotide can stop diarrhoea, facilitating the correction of electrolyte disturbance.67 As with other PET’s, complete resection is the only chance for complete cure. Even in the presence of metastatic disease, debulking may assist in the post operative management of VIP hypersecretion. Somatostatinoma Somatostatin is produced by the delta cells of the pancreas and functions in a paracrine fashion to inhibit the secretion of insulin and glucagon from pancreatic islet cells. Also, it inhibits cholecystkinin mediated release of pancreatic enzymes. With these functions in mind, hypersecretion of somatostatin presents with diabetes, malabsorption, steatorrhoea, and cholelithiasis due to reduced gallbladder contractility. These symptoms are relatively non-specific and thus the majority of somatostatinomas are diagnosed incidentally68 and confirmed with a fasting somatostatin level >14 mol/L. Metastases are frequently found at presentation.69 329 Treatment for metastatic disease Surgery offers the only curative treatment by excising the primary tumour and all lymph node metastases. In a retrospective analysis by Kazanijian et al.70 a 5 year survival of 77% was noted in patients with PET’s. The presence of lymph node metastases did not adversely affect prognosis. The survival following curative resection for ZES may be as high as 86%.59 The surgical procedures performed vary from enucleation, distal pancreatectomy and pancreaticoduodenectomy. As long term survival can be expected, even in the presence of lymph node metastases, quality-oflife post surgical resection needs to be considered. However as >60% of non-insulinoma pancreatic neuroendocrine tumours will have metastasized at the time of presentation,71,72 in the majority of cases treatment will be palliative. Even when the tumour is unresectable, intervention may reduce tumour burden and control symptoms due to obstruction or hormone over secretion. Medical management of islet cell carcinomas using streptozocin based regimens may have response rates of up to 30e70%. Somatostatin analogues may improve symptoms by reducing the amount of circulating active peptide hormones,73 however the disease may eventually become refractory to such treatment. Alternative interventions include hepatic artery embolisation and chemoembolisation. Hepatic metastases receive the majority of their blood supply from the hepatic artery, with normal hepatic tissue receiving its blood from the portal system, thus enabling more targeted therapy. By selective cannulation of the hepatic artery, chemotherapeutic agents can be delivered to the metastatic lesion prior to embolisation of the vessel. Many of the studies on hepatic artery embolisation use mixed carcinoid and PET’s with carcinoid having an inherent better prognosis. However in a study by Gupta et al. of 54 patients with pancreatic islet cell tumours, the addition of intra-arterial chemotherapy to hepatic artery embolisation improved outcome.74 Conclusion Pancreatic neuroendocrine tumours, although uncommon, as a group pose may dilemmas in diagnosis (especially in non-functional PET’s), localization and treatment. Surgery remains the only potential curative treatment; however long-term survival can be expected even in the presence of metastases. With advances in medical management, radiolabelled somatostatin therapy, hepatic arterial chemoembolisation and radiofrequency ablation, symptoms may be controlled to optimize quality of life. Conflict of interest The authors have no conflict of interest. 330 H.L. O’Grady, K.C. Conlon / EJSO 34 (2008) 324e332 Investigations Multidetector, dual phase CT, Endoscopic ultrasound ± FNA cytology Localised disease Metastatic disease Surgery Staging Laparoscopy + Intraoperative Ultrasound • Enucleation (where possible) • Distal, splenic preserving pancreatectomy • Pancreaticoduodenectomy • Duodenotomy (gastrinoma) Liver only Diffuse Observation Chemotherapy Somatostatin Isolated Observation Hepatic resection Hepatic artery embolisation Diffuse Observation Chemotherapy systemic Intra-arterial chemoembolisation Appendix WHO classification of gastroenteropancreatic neuroendocrine neoplasms Site Pancreas Well differenciated Well differenciated Well differenciated Poorly differenciated , Endocrine tumour , (Benign behaviour) , Endocrine tumour , (Uncertain behaviour) , endocrine carcinoma , (Low grade malignant) , endocrine carcinoma , (High grade malignant) Confined to pancreas <2 cm Confined to pancreas 2 cm Small cell carcinoma Necrosis common <2 mitoses per 10 HPF >2 mitoses per 10 HPF <2% Ki-67 positive cells No vascular invasion >2% Ki-67 positive cells or vascular invasion Well to moderately differentiated Gross local invasion and/or metastases Mitotic rate often higher (2e10 per 10 HPF) Ki-67 index >5% >10 mitoses per 10 HPF >15% Ki-67 positive cells Prominent vascular and/or perineural invasion Stomach Confined to mucosa-submucosa, Confined to mucosa-submucosa, Well to moderately differentiated Small cell carcinoma 1 cm. No vascular invasion >1 cm or vascular invasion Invasion to muscularis propria or beyond or metastases Duodenum, upper Confined to mucosa-submucosa, Confined to mucosa-submucosa, Well to moderately differentiated Small cell carcinoma jejunum 1 cm. No vascular invasion >1 cm or vascular invasion Invasion to muscularis propria or beyond or metastases Ileum, colon, rectum Confined to mucosa-submucosa, Confined to mucosa-submucosa, Well to moderately differentiated Small cell carcinoma 1 cm (small intestine) >1 cm (small intestine) Invasion to muscularis propria or beyond or metastases 2 cm (large intestine). >2 cm (large intestine) or No vascular invasion vascular invasion Appendix Non-functioning Enteroglucagon-producing Well to moderately differentiated Small cell carcinoma Confined to appendiceal wall Confined to subserosa Invasion to mesoappendix or beyond or metastases 2 cm. No vascular invasion >2 cm or vascular invasion References 1. Moldow RE, Connolly RR. 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