Neuroendocrine Tumors of The Pancreas NETP or Pancreatic Endocrine Tumor PET

1. Neuroendocrine Tumors of The Pancreas (NETP) or Pancreatic Endocrine Tumor (PET) Chien-Wen Chou MD. Endocrinology and Metabolism Division Chi-Mei Medical Center 13 April 2007

2. Introduction (1) Uncommon tumors Approximately 1 in 100 000 Only 1�2% of pancreatic neoplasms No gender predilection Found in all age groups with a peak incidence between 30�60 years of age Islet cell tumor Arise from multipotent stem cells in the ductal epithelium

3. Introduction (2) Between 30�50% of MEN I and 15% of von-Hippel Lindau patients will develop NETP NETP belonging to MEN I syndrome present with deletions on chromosome 11q13, the site of the MENIN gene. Somatic mutations on the long arm of chromosome 11 have been found in 20% of sporadic NETP The gene associated with von-Hippel Lindau located on chromosome 3p25.2 does not appear to be involved in the development of sporadic NETP

4. Introduction (3) Functioning tumors With Insulinomas being the most frequent type (up to 70%), followed by gastrinomas are the two commonest functioning NETP Insulinomas alone, an incidence of approximately 4 tumors per 1 million patient-years. The remaining rare functioning NETP include glucagonoma, VIPomas (watery diarrhea, hypokalemia, achlorhydria), somatostatinomas, pancreatic carcinoids (serotonin), ectopic hypercalcemia syndrome (PTH-rP), and ACTH-secreting NETP (Cushing syndrome). Syndromic or functioning PETs make up 60% Nonfunctioning NETP may still show elevated hormone levels in the blood and immunoreactivity on histological specimens Hormones that to date do not appear to have a clinical syndrome when found in excess in the blood include PP, neurotensin, CgA and the newly discovered ghrelin, which is a growth hormone secratogue. Up to 40% of NETP are nonfunctioning.

6. Biologic Behavior PETs are potentially malignant neoplasms. with 50�60% having already spread to the liver at presentation. Among the functioning tumors, most insulinomas show benign behavior. other types of functioning tumors fall either into the category of well-differentiated tumors with uncertain behavior (10%�15%) or, more frequently, that of well-differentiated carcinomas (approximately 85%�90%). Most of nonfunctioning tumors are well-differentiated carcinomas (90%�95%). Poorly differentiated endocrine carcinomas are uncommon In general, malignant metastasizing PETs are slowly growing neoplasms. Survival from the time of diagnosis usually ranges between 2 and 10 years. In sporadic metastasizing gastrinomas, survival is longer if the tumor arises from the duodenum than from the pancreas. MEN1-associated tumors of the pancreas are rarely metastatic, in contrast to those of the duodenum

7. Pathological Classification and Biochemical Diagnosis The histological criteria are the degree of differentiation, the size of the tumor, the presence or absence of angioinvasion and the proliferation index. This classification differentiates between well-differentiated, mostly benign endocrine tumors with an excellent prognosis (such as insulinomas), well-differentiated neuroendocrine carcinomas with a low malignant potential and a favorable prognosis (some gastrinomas), and poorly-differentiated highly malignant neuroendocrine carcinomas with a poor prognosis (many nonfunctioning NETP) There are general tumor markers that are released by both functioning and nonfunctioning NETP, these include CgA, PP and hCG. CgA is elevated in 50�80% of NETP, and has been shown to correlate with overall disease burden

9. Somatostatin Recetpors Many neuroendocrine tumors, including PETs, express somatostatin receptors. Five types of these receptors have been identified (eg, SSTR1-5). They can be demonstrated by autoradiography, by scintigraphic imaging (OctreoScan) or by immunohistochemistry. In PETs, the immunohistochemical expression of SSTR2, which shows a membranous pattern, correlates closely with the OctreoScan signals (Fig. 1). In the group of functioning PETs, gastrinomas are more commonly positive for SSTR2/5 (up to 90%) than insulinomas are (up to 60%).

11. Morphologic Features Macroscopy

12. Morphologic Features Histology

13. Immunophenotyping Markers of the neuroendocrine phenotype, such as synaptophysin, chromogranins A, B, and C, HISL-19, neuron-specific enolase (NSE), the proprotein convertases PC2 and PC3, the lymphoreticular epitope Leu-7, and the neural cell adhesion molecule (NCAM or CD56), reveal the neuroendocrine differentiation of PETs, independent of hormone production. NSE represents a cytoplasmic protein, while synaptophysin belongs to a complex family of small vesicle membrane proteins, which also includes synaptobrevin, SV2, and SNAP25. The staining intensity of these markers is independent of the content of secretory granules in the cells or the type of hormone produced (Fig. 4A). antibodies and antisera directed against the chromogranins, HISL-19, Leu-7, prealbumin, and pancreastatin recognize components of neurosecretory granules, and thus their staining intensity depends on the granule content (eg, grade of differentiation) of the cells (Fig. 4B). The chromogranin A immunoreactivity roughly parallels the results of silver staining techniques applied for the detection of argyrophilia. In addition to neuroendocrine markers, PETs stain for cytokeratins 8, 18, and 19 but rarely for cytokeratin 7 and neurofilament proteins

15. Criteria of Malignancy Gross invasion of adjacent organs and lymph node or liver metastases are unequivocal evidence of malignancy in PETs, and poor histologic differentiation with a high degree of cellular anaplasia and features of a small cell carcinomas is a good indication of malignancy (see Table 3). metastasis may not occur until many years after the surgical excision of the primary. in well-differentiated tumors, tumor size (>2�3 cm), tumor necrosis, microinvasion of lymphatic vessels, blood vessels or nerves, a high mitotic index (ie, >2 per 10 HPF) and high proliferative activity (ie, Ki-67/MIB-1 indices greater than 2 and PCNA indices greater than 5%) and tumor biology (insulinoma versus noninsulinomas) are strongly correlated with malignant behavior (Table 2). Recently cytokeratin 19 and the entrapment of islets were found to correlate with malignancy. DNA analysis (ploidy pattern),staining for AgNORs and expression of oncogene products, progesterone receptor, laminin receptor, and the [alpha] chain of human chorionic gonadotropin (HCG-a) are of minor prognostic

17. Specific Tumor Types Insulinomas Gastrinomas Glucagonomas Vipomas Somatostatinomas Functioning Tumors Producing Ectopic Hormones or Multiple Hormones Nonfunctioning Tumors PET in MEN Type 1 Mixed Endocrine-Exocrine Tumors

18. Insulinomas The peak incidence is found between 40 and 60 years. Virtually all insulinomas are found in the pancreas. They are distributed almost evenly throughout the pancreas or are attached to it such tumors have been observed in the duodenum, ileum, lung, cervix and ovary. Between 85% and 99% of insulinomas are benign, solitary, and less than 2.5 cm in diameter when detected Insulinomas that turn out to be malignant usually have a diameter of over 3 cm, and about one third have metastasized at the time of diagnosis. Multiple insulinomas, occurring synchronously or metachronously, are found in 2%�7% of the patients, and MEN1-associated insulinomas in 6%

20. Gastrinomas Inappropriate gastrin secretion by gastrinomas causes the Zollinger-Ellison syndrome (ZES). This is characterized by gastric acid hypersecretion, reflux disease, intractable peptic ulceration, and occasionally severe diarrhea. Between 60% and 75% of patients with ZES are found to have the syndrome as an isolated disease (sporadic ZES); in the remaining patients, ZES is part of the MEN1 Gastrinomas are second only in incidence to insulinomas and are most often malignant. The peak incidence of gastrinomas lies between 40 and 50 years; children (5�15 years of age) are rarely affected Around 90% of the gastrinomas associated with the MEN1 syndrome reside in the duodenum (Fig. 8). These tumors are usually smaller than 1 cm and multicentric and arise from gastrin-cell-precursor lesions Currently, duodenal gastrinomas are more frequently found in the duodenum and clearly outnumber pancreatic gastrinomas by 4:1 to 5:1

22. Glucagonomas This syndrome includes a rash known as necrolytic migratory erythema, mild glucose intolerance, normochromic normocytic anemia, weight loss, depression, and a tendency to develop deep vein thrombosis rather large (size range, 2�35 cm), commonly occur in the distal portion of the pancreas or attached to the pancreas most often malignant

23. Vipomas causes the watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome, also called Verner-Morrison syndrome In the adult, most of vipomas are of pancreatic origin. Exceptions are some rare VIP-producing pheochromocytomas and intestinal endocrine tumors. In children, WDHA syndromes have been reported in association with VIP-secreting ganglioneuromas and ganglioneuroblastomas usually solitary large tumors (mean size, 4�5 cm), occur often in the pancreas tail (approximately 50%), and are malignant in at least 80% of cases

24. Somatostatinomas In 1979, the somatostatinoma syndrome was described in patients presenting with symptoms of diabetes mellitus, cholecystolithiasis, steatorrhea, indigestion, hypochlorhydria, and occasionally anemia also at other sites, particularly the duodenum 50% of the cases, malignant occasional psammomatous calcifications most often at the site of the papilla of Vater or in close proximity to it Some of these tumors were associated with neurofibromatosis type 1 and ZES/MEN1

25. Functioning Tumors Producing Ectopic Hormones or Multiple Hormones due to the production of ACTH (Cushing syndrome), serotonin (carcinoid syndrome), growth hormone-releasing factor (acromegaly), PTH-related protein (PTHrP) mimicking the action of PTH (paraneoplastic hypercalcemia), and calcitonin (diarrhea in 50% of the cases). Most of these particular neoplasms were malignant and of large size. Combinations of various hormonal syndromes or transitions from one syndrome to another have been described

26. Nonfunctioning Tumors The majority of surgically removed nonfunctioning tumors are more than 5 cm in diameter and show malignant behavior. Their symptoms are related either to the appearance of metastases or to their size and site. The explanation for the lack of hormonally induced syndromes in these PETs may be (1) the low amount of hormone(s) produced and released (2) the biologic ineffectiveness of the principal hormone synthesized and secreted by the tumor, as is the case with PPomas and neurotensinomas (3) the secretion by the tumor of a precursor hormone that is functionally inert.

27. PET in MEN Type 1 In MEN, PETs are part of a tumor spectrum that involves the parathyroid glands (80%�98% of patients), the anterior pituitary (9%�40%) and the duodenum (40%�85%) but occasionally also the stomach, lung, or thymus pancreatic lesions in MEN1 is diffuse microdenomatosis in association with 1 or several macrotumors (above 0.5 cm in diameter).

28. Localization Studies Biphasic computed tomography scan of the pancreas and liver with water as the oral contrast agent, and magnetic resonance imaging of the pancreas and liver. Endoscopic ultrasound Indium-111 octreotide scintigraphy I 131mIBG (metaiodobenzylguanidine) scanning has a sensitivity of less than 10% for these tumors Positron emission tomography (PET) scanning 5-hydroxytryptophan labeled with 11C reveals more than 95% of NETP

29. Surgical Treatment (1) Prior to surgery, symptoms of hormone over-production must be treated. This includes fluid and electrolyte resuscitation in patients with diarrhea (glucagonoma and VIPoma). Insulinoma patients should have sugars controlled using diet, octreotide and diazoxide when needed. Gastrinoma patients require control of acid overproduction using proton pump inhibitors and octreotide. Severely malnourished patients may require supplemental nutrition prior to surgical therapy all tumors (except for insulinomas, some gastrinomas and small lesions less than 2 cm) have a high likelihood of being malignant. NETP should undergo an oncologic pancreatic resection including the surrounding lymph nodes. For lesions in the head and neck and of the pancreas, this involves a Whipple operation lesions to the left of the superior mesenteric vein�portal vein confluence should undergo a distal pancreatic resection and splenectom

30. Surgical Treatment (2) As the majority of insulinomas are benign (90%), these tumors should be treated with enucleation when possible. Laparoscopic resection of these tumors has recently been described. In cases where there is a suspicion of malignancy, including local invasion and/or tumors > 5cm in size, formal pancreatic resection should be performed 50% of gastrinomas will prove to be malignant especially when they exceed 5cm in size. Locoregional lymph nodes should be assessed intraoperatively

31. Surgical Treatment (Liver Metastasis) In patients with metastatic disease of the liver, the goals of therapy are to control and/or eliminate tumor growth, as well as to diminish excess hormone production As with all metastatic tumors of the liver, surgical resection is considered the treatment of choice when possible. The utilization of other forms of cytoreduction such as radiofrequency ablation and embolization have increased our ability to debulk metastatic liver lesions most patients will recur within the first 2 years following resection Some patients with apparently nonfunctioning NETP, however, will progress over time to display an endocrinopathy with progressive growth of the tumor In patients that demonstrate radiotracer uptake of octreotide or MIBG by tumor deposits, our strategy is tumor debulking with postoperative adjuvant therapy

32. Surgical Treatment (MEN 1) Surgical cure is rarely if ever possible without complete pancreatectomy because of the diffuse adenomatous disease seen through the pancreas. Treatment of NETP in MEN I was focused on the management of various functional syndromes.

33. Nonsurgical Treatment Chemotherapy Somatostatin analogues Interferon-alfa Radiolabeled therapy

34. Chemotherapy NET are in general chemoresistant. NET arising from the pancreas, however, appear to be the most responsive. Streptozocin combination regimes (streptozocin and doxorubicin) achieve a favorable, but short lived response in up to 60% of patients Streptozocin is a glucosamine-nitrosurea compound that induces degranulation of islet b-cells. Dacarbazine monotherapy has also shown response rates up to 40% The combination of etoposide and cisplatin in NETP has been used with limited short-lived response rates

35. Somatostatin Analogues Symptomatic along with biochemical response to somatostatin analogue therapy occurs in between 60�90% of patients The median duration of response, however, is on average only 12 months, at which time tachyphylaxis often develops. Somatostatin analogues inhibit not only hormone release, but also play a role in inhibiting angiogenesis. Between 5�15% of patients will have a reduction in tumor burden. The future developments of subtype receptor-specific analogues show promise Targeting somatostatin receptor subtype 3, which is involved in angiogenesis

36. Interferon-alfa Interferon acts through both direct antiproliferative effects as well as inhibition of tumor angiogenesis mediated by suppression of VEGF gene expression in NETP interferon has shown a 50% biochemical response for a median duration of 20 months Tumor response occurs in only 10�15% of patients, however, tumor stabilization is reported in 40�60% of patients. Side effects include flu-like symptoms, arthralgias and depression.

37. Radiolabeled therapy Tumor uptake with 111In-octreotide was seen in 61% of insulinomas, and 100% of the gastrinomas studied To date, prospective survival benefit has not been demonstrated, however, improvement in quality of life for these patients The recent development of other radiolabeled somatostatin analogues coupled with 90Y and 177Lu

38. Prognosis NETP have a more indolent course, with a concomitantly better outcome when compared with pancreatic adenocarcinoma. Prognosis depends on a combination of factors including histopathologic differentiation, size of the tumor, and the associated syndrome. Using the Surveillance, Epidemiology, and End Results (SEER) program, over 13 000 NET of the gastrointestinal tract were examined The overall 5-year survival was 50.4%. The presence of regional and distant disease reduced this to 21.8%. When classified by site of origin, foregut tumors (including pancreas) had a 5-year survival of 44.5% (61% midgut, 72% hindgut). Other possible prognostic indicators being studied include expression of Ki-67, p53, oncoprotein, tumor-suppressor genes, and adhesion molecules A low expression of Ki-67, a histopathologic proliferation marker, predicts slow tumor growth and a more favorable prognosis

39. References Elijah Dixon and Janice L. Pasieka Functioning and nonfunctioning neuroendocrine tumors of the pancreas. [Review] Current Opinion in Oncology. 19:30-35, 2007  Gunter Kloppel and Martin Anlauf Pancreatic Endocrine Tumors Pathology Case reviews 2006; 11:256-267