Di Florio A, Sancho V, Moreno P, et al.
Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor.
Biochim Biophys Acta. 2013; 1833(3):573-82 [PubMed] Article available free on PMC after 01/03/2014

Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor,Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr(1068) EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs.

Atema JJ, Amri R, Busch OR, et al.
Surgical treatment of gastrinomas: a single-centre experience.
HPB (Oxford). 2012; 14(12):833-8 [PubMed] Article available free on PMC after 01/12/2013

BACKGROUND: Gastrinomas are rare neuroendocrine tumours, and responsible for Zollinger-Ellison syndrome (ZES). Surgery is the only treatment that can cure gastrinomas. The success of surgical treatment of gastrinomas in a single centre was evaluated.
METHODS: A retrospective review of all patients who underwent resection for a gastrinoma between 1992 and 2011 at a single institution was performed. Presentation, diagnostics, operative management and outcome were analysed.
RESULTS: Eleven patients with a median age of 46 years were included. All patients had fasting hypergastrinaemia and a primary tumour was localized using imaging studies in all patients. A pylorus-preserving pancreaticoduodenectomy was performed in three patients: two patients underwent duodenectomy and one patient central pancreatectomy. The remaining five patients underwent enucleation. A primary tumour was removed in nine patients: five tumours were situated in the pancreas, three in the duodenum and one patient was considered to have a primary lymph node gastrinoma. The median follow-up was 3 years (range 1-15) after which 7 patients were disease-free and 3 patients had (suspected) metastatic disease. One patient died 13 years after initial surgery.
CONCLUSION: The success of surgical treatment of a gastrinoma in this series was 7/11 with a median follow-up of 3 years; comparable to recent published studies.

Rui M, Li L, Jiang-Feng M, et al.
Hypercalcemia appeared in a patient with glucagonoma treated with octreotide acetate long-acting release.
Chin Med Sci J. 2012; 27(3):182-4 [PubMed]

PABCREATIC neuroendocrine tumours are uncommon neoplasms of the pancreas. They may cause a clinical syndrome due to hormone overproduction. Glucagonoma is a rare kind of pancreatic tumors. Here we report a case of glucagonoma. Hypercalcemia occurred when the patient underwent octreotide acetate long-acting release.

Melcescu E, Hogan RB, Brown K, et al.
The various faces of autoimmune endocrinopathies: non-tumoral hypergastrinemia in a patient with lymphocytic colitis and chronic autoimmune gastritis.
Exp Mol Pathol. 2012; 93(3):434-40 [PubMed]

Serum gastrin levels exceeding 1000pg/ml (normal, <100) usually raise the suspicion for a neuroendocrine tumor (NET) that secretes gastrin. Rarely, such elevated gastrin levels are seen in patients with pernicious anemia which most commonly is associated with autoimmune gastritis (AG). AG can occur concomitantly with other autoimmune disorders including lymphocytic colitis (LC). Gastrin stimulates enterochromaffin-like cells which increase histamine secretion. Histamine excess can cause diarrhea as can bacterial overgrowth or LC. We present a 57-year-old woman with diarrhea, sporadic epigastric pain, and bloating. She also had a history of interstitial cystitis and took pentosan polysulfate and cetirizine. She had no history of ulcers, renal impairment or carcinoid syndrome. Fasting serum gastrin was 1846pg/ml. Esophagoduodenal gastroscopy and biopsies revealed chronic gastritis and a pH of 7 with low stomach acid. Serum gastrin and plasma chromogranin A were suggestive of a gastrinoma or NET. Pernicious anemia was unlikely. Imaging studies did not reveal any tumor. Random colonic biopsy was compatible with LC, possibly explaining her diarrhea, although we also considered excessive histamine from elevated gastrin, bacterial overgrowth, and pentosan polysulfate which can cause diarrhea and be misleading in this setting, pointing to the diagnosis of gastrinoma. At 4year follow-up in 2012, fasting serum gastrin was 1097pg/ml and the patient asymptomatic taking only cetirizine for nasal allergies. This case illustrates that diarrhea may be associated with very high serum gastrin levels in the setting of chronic gastritis, LC, and interstitial cystitis (pentosan use), without clear evidence for a gastrinoma or NET. If no history of ulcers or liver metastases is present in such cases, watchful observation rather than an extensive/invasive and costly search for a NET may be justified. Considering the various forms of polyglandular syndrome, this may represent a variant and we here provide an algorithm for working up such patients, while also reviewing literature on the intertwined relationship between the immune and endocrine systems.

Fung MA, Barr KL
Current knowledge in inflammatory dermatopathology.
Dermatol Clin. 2012; 30(4):667-84, vii [PubMed]

The complex and fascinating spectrum of inflammatory skin disease, and the comprehension of it, is ever expanding and evolving. During the first decade of the 21st century, numerous advances in the understanding of inflammatory disease mechanisms have occurred, particularly in psoriasis and atopic dermatitis. Continuation of this trend will assure a future in which molecular tests for biomarkers of immediate clinical relevance are used in routine patient care, not only for diagnosis but also for prognosis and management. This article focuses on selected recent or noteworthy developments that are clinically relevant for the histologic diagnosis of inflammatory skin diseases.

Kidd M, Gustafsson BI
Management of gastric carcinoids (neuroendocrine neoplasms).
Curr Gastroenterol Rep. 2012; 14(6):467-72 [PubMed]

Gastric neuroendocrine neoplasms of the stomach can be divided into the usually well-differentiated, hypergastrinemia-dependent type I and II lesions and the more aggressively behaving gastrin-independent type III lesions. Mainly due to better diagnostics and awareness of this tumor, the observed incidence has increased more than tenfold over the last 30 years. Small (<15-20 mm) localized type I and II lesions that are slowly proliferating (Ki67<2%) can usually be managed conservatively with endoscopic surveillance. Reducing hypergastrinemia by surgical removal of an underlying gastrinoma is important in inhibiting growth and induce reduction of type II lesions, while the specific gastrin receptor antagonist YF476 or gastrin antibodies may become useful for both type I and II lesions. Infiltrating and metastasized tumors and type III lesions require a more aggressive approach with surgical resection and consideration of modalities such as somatostatin analogs, cytotoxics, and peptide receptor targeted treatment.

Sugiyama T, Nakanishi M, Hoshimoto K, et al.
Severely fluctuating blood glucose levels associated with a somatostatin-producing ovarian neuroendocrine tumor.
J Clin Endocrinol Metab. 2012; 97(11):3845-50 [PubMed]

CONTEXT: Somatostatin-producing tumors are a rare type of neuroendocrine tumor. Their effects on blood glucose levels have been variously reported, and detailed reports have been scarce.
OBJECTIVE: The aim of this study was to identify the reasons for the extraordinary blood glucose fluctuations in a case with no previous history of diabetes.
PATIENTS AND METHODS: A 68-yr-old nondiabetic woman with an ovarian tumor was suffering from hyper- and hypoglycemia. Based on the results of an oral glucose tolerance test and continuous glucose monitoring, we speculated that the fluctuating blood glucose level was accompanied not only by a low insulin level but also by low counter-regulatory hormones levels, and that those broad hormonal suppressions were caused by a high somatostatin level produced in the ovarian tumor. We performed an oophorectomy and assessed the pathology of the tumor and changes in the blood glucose profile as well as hormonal levels postoperatively.
RESULTS: The blood glucose level was completely normalized after the oophorectomy. Insulin secretion was also normalized. Histological examination showed that the tumor comprised a mature cystic teratoma and a stromal carcinoid. Immunohistochemically, the stromal carcinoid component was positive for somatostatin. The somatostatin level was 8505 pmol/liter preoperatively, which dropped down to 71.5 pmol/liter postoperatively. We found two previous reports of somatostatin-producing ovarian neuroendocrine tumors. Somatostatin levels among cases of ovarian origin were much higher than those among cases of gastrointestinal origins, and cases of ovarian origin all experienced blood glucose fluctuations.
CONCLUSION: Extremely high somatostatin levels and blood glucose fluctuations may be characteristics of somatostatin-producing ovarian neuroendocrine tumors.

Zhuang Z, Yang C, Lorenzo F, et al.
Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia.
N Engl J Med. 2012; 367(10):922-30 [PubMed] Article available free on PMC after 01/12/2013

Hypoxia-inducible factors are transcription factors controlling energy, iron metabolism, erythropoiesis, and development. When these proteins are dysregulated, they contribute to tumorigenesis and cancer progression. However, mutations in genes encoding α subunits of hypoxia-inducible factors (HIF-α) have not previously been identified in any cancer. Here we report two novel somatic gain-of-function mutations in the gene encoding hypoxia-inducible factor 2α (HIF2A) in two patients, one presenting with paraganglioma and the other with paraganglioma and somatostatinoma, both of whom had polycythemia. The two mutations were associated with increased HIF-2α activity and increased protein half-life.

Killingsworth MC, Lai K, Wu X, et al.
Quantum dot immunocytochemical localization of somatostatin in somatostatinoma by Widefield Epifluorescence, super-resolution light, and immunoelectron microscopy.
J Histochem Cytochem. 2012; 60(11):832-43 [PubMed] Article available free on PMC after 01/11/2013

Quantum dot nanocrystal probes (QDs) have been used for detection of somatostatin hormone in secretory granules of somatostatinoma tumor cells by immunofluorescence light microscopy, super-resolution light microscopy, and immunoelectron microscopy. Immunostaining for all modalities was done using sections taken from an epoxy resin-embedded tissue specimen and a similar labeling protocol. This approach allowed assessment of labeling at light microscopy level before examination at super-resolution and electron microscopy level and was a significant aid in interpretation. Etching of ultrathin sections with saturated sodium metaperiodate was a critical step presumably able to retrieve some tissue antigenicity masked by processing in epoxy resin. Immunofluorescence microscopy of QD-immunolabeled sections showed somatostatin hormone localization in cytoplasmic granules. Some variable staining of tumor gland-like structures appeared related to granule maturity and dispersal of granule contents within the tumor cell cytoplasm. Super-resolution light microscopy demonstrated localization of somatostatin within individual secretory granules to be heterogeneous, and this staining pattern was confirmed by immunoelectron microscopy.

Norton JA, Fraker DL, Alexander HR, Jensen RT
Value of surgery in patients with negative imaging and sporadic Zollinger-Ellison syndrome.
Ann Surg. 2012; 256(3):509-17 [PubMed] Article available free on PMC after 01/09/2013

OBJECTIVES: To address the value of surgery in patients with sporadic Zollinger-Ellison syndrome (ZES) with negative imaging studies.
BACKGROUND: Medical control of acid hypersecretion in patients with sporadic ZES is highly effective. This has led to these patients frequently not being sent to surgery, especially if preoperative imaging studies are negative, due, in large part, to existence of almost no data on the success of surgery in this group.
METHODS: Fifty-eight prospectively studied patients with sporadic ZES (17% of total studied) had negative imaging studies, and their surgical outcome was compared with 117 patients with positive imaging results.
RESULTS: Thirty-five patients had negative imaging studies in the pre-somatostatin receptor scintigraphy (SRS) era, and 23 patients in the post-SRS era. Patients with negative imaging studies had long disease histories before surgery [mean ± SEM (from onset) = 7.9 ± 1 [range, -0.25 to 35 years]) and 25% were followed for 2 or more years from diagnosis. At surgery, gastrinoma was found in 57 of 58 patients (98%). Tumors were small (mean = 0.8 cm, 60% <1 cm). The most common primary sites were duodenal 64%, pancreatic 17%, and lymph node (10%). Fifty percent had a primary-only, 41% primary + lymph node, and 7% had liver metastases. Thirty-five of 58 patients (60%) were cured immediately postoperatively, and at last follow-up [mean = -9.4 years; range, 0.2-22 years], 27 patients (46%) remained cured. During follow-up, 3 patients died, each had liver metastases at surgery. In comparison to positive imaging patients, those with negative imaging studies had lower preoperative fasting gastrin levels; had a longer delay before surgery; more frequently had a small duodenal tumor; less frequently had a pancreatic tumor, multiple tumors, or developed a new lesion postoperatively; and had a longer survival.
CONCLUSIONS: Sporadic ZES patients with negative imaging studies are not rare even in the post-SRS period. An experienced surgeon can find gastrinoma in almost every patient (98%) and nearly one half (46%) are cured, a rate similar to patients with positive imaging findings. Because liver metastases were found in 7%, which may have been caused by a long delay in surgery and all the disease-related deaths occurred in this group, surgery should be routinely undertaken early in ZES patients despite negative imaging studies.

Bartsch DK, Waldmann J, Fendrich V, et al.
Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma.
Br J Surg. 2012; 99(9):1234-40 [PubMed]

BACKGROUND: The study was undertaken to determine prognostic factors and the value of systematic lymphadenectomy on survival in sporadic gastrinoma.
METHODS: Patients with sporadic gastrinoma who underwent initial surgery during a 21-year period in two tertiary referral centres were analysed retrospectively with respect to clinical characteristics, operative procedures and outcome.
RESULTS: Forty-eight patients with a median age of 52 (range 22-73) years were analysed. Some 18 patients had pancreatic and 26 had duodenal gastrinomas, whereas the primary tumour remained unidentified in four patients. After a median postoperative follow-up of 83 (range 3-296) months, 20 patients had no evidence of disease, 13 patients were alive with disease, 11 patients had died from the disease and four had died from unrelated causes. In 41 patients who underwent potentially curative surgery, systematic lymphadenectomy with excision of more than ten lymph nodes resulted in a higher rate of biochemical cure after surgery than no or selective lymphadenectomy (13 of 13 versus 18 of 28 patients; P = 0·017), with a trend towards prolonged disease specific survival (P = 0·062) and disease-free survival (P = 0·120), and a reduced risk of death (0 of 13 versus 7 of 24 patients; P = 0·037). Negative prognostic factors for disease specific survival were pancreatic location (P = 0·029), tumour size equal to or larger than 25 mm (P = 0·003), Ki-67 index more than 5 per cent (P < 0·001), preoperative gastrin level 3000 pg/ml or more (P = 0·003) and liver metastases (P < 0·001). Sex, age, type of surgery and presence of lymph node metastases had no influence on disease free or disease specific survival.
CONCLUSION: In sporadic gastrinoma, systematic lymphadenectomy during initial surgery may reduce the risk of persistent disease and improve survival.

Constantinoiu S, Constantin A, Predescu D, et al.
Somatostatinoma of the first jejunal loop in a patient with neurofibromatosis von Recklinghausen and bilateral pheochromocytoma.
Hepatogastroenterology. 2012; 59(118):1874-8 [PubMed]

Somatostatinoma is a rare neuroendocrine tumor which especially develops in the pancreas. There are few communicated cases about extra-pancreatic localization, having as a particularity the absence of somatostatin hypersecretion syndrome and frequent association with von Recklinghausen neurofibromatosis. We present the case of a 42-year old patient with Von Recklinghausen neurofibromatosis admitted in our clinic with a chronic upper digestive obstruction syndrome. The presence of a first jejunal loop somatostatinoma was an intraoperative surprising diagnosis that imposed jejunal resection and association of complementary specific treatment. Despite the therapeutic correct management, the status of the patient deteriorated very fast, confirming the aggressiveness of this neoplasia.

Bellemann N, Stampfl U, Sommer CM, et al.
Portal vein embolization using a Histoacryl/Lipiodol mixture before right liver resection.
Dig Surg. 2012; 29(3):236-42 [PubMed]

PURPOSE: The purpose of this retrospective study was to evaluate the efficacy and safety of percutaneous transhepatic portal vein embolization (PVE) of the right liver lobe using Histoacryl/Lipiodol mixture to induce contralateral liver hypertrophy before right-sided (or extended right-sided) hepatectomy in patients with primarily unresectable liver tumors.
METHODS: Twenty-one patients (9 females and 12 males) underwent PVE due to an insufficient future liver remnant; 17 showed liver metastases and 4 suffered from biliary cancer. Imaging was performed prior to and 4 weeks after PVE. Surgery was scheduled for 1 week after a CT or MRI control. The primary study end point was technical success, defined as complete angiographical occlusion of the portal vein. The secondary study end point was evaluation of liver hypertrophy by CT and MRI volumetry and transfer to operability.
RESULTS: In all the patients, PVE could be performed with a Histoacryl/Lipiodol mixture (n = 20) or a Histoacryl/Lipiodol mixture with microcoils (n = 1). No procedure-related complications occurred. The volume of the left liver lobe increased significantly (p < 0.0001) by 28% from a mean of 549 ml to 709 ml. Eighteen of twenty-one patients (85.7%) could be transferred to surgery, and the intended resection could be performed as planned in 13/18 (72.3%) patients.
CONCLUSION: Preoperative right-sided PVE using a Histoacryl/Lipiodol mixture is a safe technique and achieves a sufficient hypertrophy of the future liver remnant in the left liver lobe.

Carşote M, Păun S, Neamţu MC, et al.
The immunohistochemistry aspects in two cases of neurofibromatosis-associated abdominal tumors.
Rom J Morphol Embryol. 2012; 53(2):401-5 [PubMed]

Type 1 neurofibromatosis associates various abdominal tumors as gastrointestinal stromal tumors, duodenal or pancreatic carcinoid, and adrenal tumors like pheochromocytoma. We present the immunohistochemistry report in two cases with different profile regarding the evolution. One case is a 7th decade women diagnosed with unilateral pheochromocytoma and GISTs, with a good prognosis after surgery. The other case is a 41-year-old male diagnosed with duodenal metastatic somatostatinoma after an intestinal occlusive syndrome and later the hormonal profile leaded to the diagnosis of pheochromocytoma. The patient had a fulminate evolution within six months from diagnosis.

Machado MC
Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1.
Clinics (Sao Paulo). 2012; 67 Suppl 1:145-8 [PubMed] Article available free on PMC after 01/09/2013

Surgical approaches to pancreatic endocrine tumors associated with multiple endocrine neoplasia type 1 may differ greatly from those applied to sporadic pancreatic endocrine tumors. Presurgical diagnosis of multiple endocrine neoplasia type 1 is therefore crucial to plan a proper intervention. Of note, hyperparathyroidism/multiple endocrine neoplasia type 1 should be surgically treated before pancreatic endocrine tumors/multiple endocrine neoplasia type 1 resection, apart from insulinoma. Non-functioning pancreatic endocrine tumors/multiple endocrine neoplasia type 1 >1 cm have a high risk of malignancy and should be treated by a pancreatic resection associated with lymphadenectomy. The vast majority of patients with gastrinoma/multiple endocrine neoplasia type 1 present with tumor lesions at the duodenum, so the surgery of choice is subtotal or total pancreatoduodenectomy followed by regional lymphadenectomy. The usual surgical treatment for insulinoma/multiple endocrine neoplasia type 1 is distal pancreatectomy up to the mesenteric vein with or without spleen preservation, associated with enucleation of tumor lesions in the pancreatic head. Surgical procedures for glucagonomas, somatostatinomas, and vipomas/ multiple endocrine neoplasia type 1 are similar to those applied to sporadic pancreatic endocrine tumors. Some of these surgical strategies for pancreatic endocrine tumors/multiple endocrine neoplasia type 1 still remain controversial as to their proper extension and timing. Furthermore, surgical resection of single hepatic metastasis secondary to pancreatic endocrine tumors/multiple endocrine neoplasia type 1 may be curative and even in multiple liver metastases surgical resection is possible. Hepatic trans-arterial chemo-embolization is usually associated with surgical resection. Liver transplantation may be needed for select cases. Finally, pre-surgical clinical and genetic diagnosis of multiple endocrine neoplasia type 1 syndrome and localization of multiple endocrine neoplasia type 1 related tumors are crucial for determining the best surgical strategies in each individual case with pancreatic endocrine tumors.

Lu X, Aoun E, Morrissey S
Primary hepatic gastrinoma presenting as vague gastrointestinal symptoms.
BMJ Case Rep. 2012; 2012 [PubMed]

A 51-year-old Caucasian female with a 7-year history of intermittent abdominal pain and diarrhoea presented to our service. Before presentation, she had been successfully treated for Helicobacter pylori infection, but later developed new oesophageal ulcerations with exudative lesions that were positive for herpes simplex virus, and candida oesophagitis had developed. Biopsies showed chronic inactive gastritis with gastric intestinal metaplasia. MRI revealed a solid 3.4×3 cm lesion in the caudate lobe of the liver, with a 7-mm pancreatic cyst. The aspirated pancreatic cyst cytology was benign. On exploratory laporatomy, the lesion appeared confined to the caudate lobe, and a resection was performed. The pathology was consistent with a well-differentiated neuroendocrine carcinoma with vascular invasion and involvement of the liver capsule, although resection margins were negative. The patient had complete symptomatic improvement. This case re-affirms the high index of suspicion needed to make the diagnosis of gastrinoma. If caught in time, surgical removal of primary hepatic gastrinoma can be curative.

Grin A, Kim YI, Mustard R, et al.
Duodenal gastrinoma with multiple gastric neuroendocrine tumors secondary to chronic Helicobacter pylori gastritis.
Am J Surg Pathol. 2012; 36(6):935-40 [PubMed]

Helicobacter pylori (HP) has been associated with neuroendocrine tumors of the stomach and duodenum. Gastric enterochromaffin-like (ECL) cell tumors and duodenal gastrinomas have also been associated with HP gastritis in separate series but have not been reported together. With other possible causes excluded, we present a patient with HP-associated atrophy of the oxyntic mucosa that ultimately resulted in stimulation and reactive hyperplasia of gastrin-producing cells in both the antrum and proximal duodenum, the latter progressing to formation of a gastrin-producing cell nodule (gastrinoma). Both of these sources of gastrin resulted in ECL hyperplasia in the atrophied oxyntic mucosa with progression to microcarcinoids and well-differentiated neuroendocrine tumors, along with hypertrophy of residual proximal gastric parietal cells. As atrophy tends to spread from the antrum proximally, residual oxyntic mucosa was still infected with HP and offers 1 explanation for the apparent paradox of atrophic gastritis with ECL hyperplasia and neoplasia in the distal oxyntic mucosa, with proximal oxyntic mucosa showing mild hypertrophic changes in a background of typical HP gastritis.

Lopez CL, Falconi M, Waldmann J, et al.
Partial pancreaticoduodenectomy can provide cure for duodenal gastrinoma associated with multiple endocrine neoplasia type 1.
Ann Surg. 2013; 257(2):308-14 [PubMed]

OBJECTIVE: To evaluate the outcome of pancreaticoduodenectomy (PD) versus non-PD resections for the treatment of gastrinoma in multiple endocrine neoplasia type 1.
BACKGROUND: Gastrinoma in MEN1 is considered a rarely curable disease and its management is highly controversial both for timing and extent of surgery.
METHODS: Clinical characteristics, complications and outcomes of 27 prospectively collected MEN1 patients with biochemically proven gastrinoma, who underwent surgery, were analyzed with special regard to the gastrinoma type and the initial operative procedure.
RESULTS: Twenty-two (81%) patients with gastrinoma in MEN1 had duodenal gastrinomas and 5 patients (19%) had pancreatic gastrinomas. At the time of diagnosis, 21 (77%) gastrinomas were malignant (18 duodenal, 3 pancreatic), but distant metastases were only present in 4 (15%) patients. Patients with pancreatic gastrinomas underwent either distal pancreatic resections or gastrinoma enucleation with lymphadenectomy, 2 patients also had synchronous resections of liver metastases. One of these patients was biochemically cured after a median of 136 (77-312) months. Thirteen patients with duodenal gastrinomas underwent PD resections (group 1, partial PD [n = 11], total PD [n = 2]), whereas 9 patients had no-PD resections (group 2) as initial operative procedure. Perioperative morbidity and mortality, including postoperative diabetes, differed not significantly between groups (P > 0.5). All patients of group 1 and 5 of 9 (55%) patients of group 2 had a negative secretin test at hospital discharge. However, after a median follow-up of 136 (3-276) months, 12 (92%) patients of group 1 were still normogastrinemic compared to only 3 of 9 (33%) patients of group 2 (P = 0.023). Three (33%) patients of group 2 had to undergo up to 3 reoperations for recurrent or metastatic disease compared to none of group 1.
CONCLUSIONS: Duodenal gastrinoma in MEN1 should be considered a surgically curable disease. PD seems to be the adequate approach to this disease, providing a high cure rate and acceptable morbidity compared to non-PD resections.

Grewal P, Salopek TG
Is necrolytic migratory erythema due to glucagonoma a misnomer? A more apt name might be mucosal and intertriginous erosive dermatitis.
J Cutan Med Surg. 2012 Mar-Apr; 16(2):76-82 [PubMed]

BACKGROUND: In dermatology, many conditions are given names that ultimately prove to be a misnomer (eg, mycosis fungoides, pyogenic granuloma). For most misnomers, continued use of the inappropriate word(s) rarely results in a delay in diagnosis and/or treatment. An argument can be made that the term necrolytic migratory erythema (NME) due to glucagonoma results in a delay in diagnosis, often with fatal consequences.
OBJECTIVE: We reviewed the literature of the past 30 years concerning the dermatologic and histologic findings of NME in association with glucagonoma. The most striking feature evident in nearly all reported cases is the presence of mucosal lesions and annular, eroded, eczematous patches and plaques of intertriginous areas.
CONCLUSION: We propose the renaming of the eruption associated with glucagonoma to one that emphasizes its unique localization to the mucosa and intertriginous areas: mucosal and intertriginous erosive dermatitis. It is hoped that this will lead to a more timely recognition of the condition and a possible improvement in prognosis.

Kikuchi Y, Wada R, Sakihara S, et al.
Pheochromocytoma with histologic transformation to composite type, complicated by watery diarrhea, hypokalemia, and achlorhydria syndrome.
Endocr Pract. 2012 Jul-Aug; 18(4):e91-6 [PubMed]

OBJECTIVE: To describe the rare occurrence of histologic transformation of a pheochromocytoma to a composite type of tumor during a long-term follow-up, which was complicated by watery diarrhea, hypokalemia, and achlorhydria syndrome.
METHODS: We report the case of a 12-year-old girl who presented with headache, hypertension, and elevated catecholamine levels in the blood and urine. A tumor was found in the right adrenal gland and resected. When she was 15 years of age, multiple metastatic nodules were found in the lung and liver. Intensive chemotherapy was ineffective, and she underwent follow-up with conservative therapy. At 25 years of age, she complained of diarrhea. Laboratory studies revealed hypokalemia and an increase in the level of serum vasoactive intestinal polypeptide (VIP). A year later, she died of extensive metastatic disease. The primary and recurrent tumors at autopsy were histologically examined.
RESULTS: The primary tumor was pure pheochromocytoma, and the tumors at autopsy were a composite type of pheochromocytoma and ganglioneuroma. Only a few VIP-positive cells were found in the primary tumor, whereas both pheochromocytoma and ganglioneuroma cells of composite tumors were frequently positive for VIP.
CONCLUSION: Our case showed histologic transformation from pheochromocytoma to a composite type of tumor during a 14-year clinical course, which was associated with additional hormone production and a change in symptoms. Careful attention should be paid to the alteration of endocrine symptoms and hormone levels during prolonged follow-up of pheochromocytoma in young patients.

Rehfeld JF, Bardram L, Hilsted L, et al.
Pitfalls in diagnostic gastrin measurements.
Clin Chem. 2012; 58(5):831-6 [PubMed]

BACKGROUND: Gastrin measurements are performed primarily for the diagnosis of gastrin-producing tumors, gastrinomas, which cause the Zollinger-Ellison syndrome (ZES). Gastrin circulates as several bioactive peptides, however, and the peptide pattern in gastrinoma patients often deviates from normal. Therefore, it is necessary to measure all forms of gastrin.
CONTENT: Only immunoassays are useful for measurement of gastrin in plasma. The original assays were RIAs developed in research laboratories that used antibodies directed against the C terminus of gastrin peptides. Because the C-terminal tetrapeptide amide sequence constitutes the active site of gastrin peptides, these assays were well suited for gastrinoma diagnosis. More recently, however, most clinical chemistry laboratories have switched to commercial kits. Because of recent cases of kit-measured normogastrinemia in patients with ZES symptoms, the diagnostic sensitivity and analytical specificity of the available kits have been examined. The results show that gastrin kits frequently measure falsely low concentrations because they measure only a single gastrin form. Falsely high concentrations were also encountered, owing to overreactivity with O-sulfated gastrins or plasma proteins. Thus, more than half of the gastrin kits on the market are unsuited for diagnostics.
SUMMARY: Gastrinomas are neuroendocrine tumors, some of which become malignant. A delay in diagnosis leads to fulminant ZES, with major, even lethal, complications. Consequently, it is necessary that the diagnostic sensitivity of gastrin kits be adequate. This diagnostic sensitivity requires antibodies that bind the C-terminal epitope of bioactive gastrins without the influence of O-sulfation.

Maire F, Sauvanet A, Couvelard A, et al.
Recurrence after surgical resection of gastrinoma: who, when, where and why?
Eur J Gastroenterol Hepatol. 2012; 24(4):368-74 [PubMed]

BACKGROUND: Surgery prolongs survival in patients with gastrinomas, but postoperative recurrences are frequent and controversies still exist about the optimal surgical procedures.
AIM: The aim of this study is to analyze biological and morphological recurrences and to search for risk factors.
PATIENTS AND METHODS: Between 1990 and 2008, 22 patients (five with multiple endocrine neoplasia type 1) who underwent curative resection for gastrinoma were evaluated every 6 months for biological and morphological recurrences. All patients were disease-free postresection.
RESULTS: The median postoperative follow-up was 37 months (range, 7-204 months). A biological recurrence was observed in 59% of cases, after a median time of 16.5 months (range, 7-90 months). A morphological recurrence was reported in 32% of cases, in the liver (86%) or lymph nodes (43%), after a median time of 21 months (range, 8-91 months). The median delay between biological and morphological recurrence was 3 months (range, 0-69 months). At recurrence, all patients were offered a second treatment (surgical resection in 71% of cases). One and 5 year overall survival were 100 and 76%, respectively. One and 5 year biological disease-free survival (DFS) were 76 and 27%, respectively. One and 5 year morphological DFS were 90 and 62%, respectively. Tumor size of at least 20 mm (P=0.008) and pancreatic location (P=0.04) of the primary tumor had significant effect on morphological DFS. Overall survival was significantly lower in patients with primary tumor of at least 20 mm (P=0.01).
CONCLUSION: (a) Recurrence occurs in nearly two out of three patients operated upon for gastrinoma, most often detected through biological tests; (b) lymph nodes and liver are the most frequent sites of relapse and patients benefit from second treatment; (c) risk factors for recurrences are as follows: size of at least 20 mm; and the pancreatic location of the primary tumor.

Kattan J, Chemaly A, Chemaly M, et al.
Inflammatory breast cancer with refractory diarrhea: a case report.
J Med Liban. 2011 Jul-Sep; 59(3):165-7 [PubMed]

Excessive amounts of vasoactive intestinal polypeptide (VIP) cause a special clinical syndrome characterized by secretory diarrhea, hypokalemia and dehydration. A careful clinical workup of a 62-year-old female admitted for refractory diarrhea revealed a neglected inflammatory right breast ductal carcinoma with VIP hypersecretion without any localized abdominal tumor. Immunohistochemistry of the breast biopsy showed neuroendocrine characteristics with positive staining for VIP, and Octreotide scan showed hyperfixation to the right breast and axilla. Primary therapy of breast cancer with hormones and chemotherapy achieved transitory regression of diarrhea, VIP level decrease, and tumor border reduction. Bilateral modified radical mastectomy and irradiation of the tumor failed to prevent liver and bone dissemination of the disease. Once more, partial response was obtained by octreotide and salvage chemotherapy; however, the patient died from progressive disease 23 months after initial diagnosis. To our best knowledge, this unusual presentation of a breast carcinoma with related VIPoma syndrome is the first reported case in the literature.

Azemoto N, Kumagi T, Yokota T, et al.
An unusual case of subclinical diffuse glucagonoma coexisting with two nodules in the pancreas: characteristic features on computed tomography.
Clin Res Hepatol Gastroenterol. 2012; 36(3):e43-7 [PubMed]

A lesion was discovered in the tail of the pancreas by ultrasonography performed during a health checkup for a 59-year-old Japanese man. Abdominal contrast-enhanced computed tomography (CE-CT) revealed strong enhancement in a 4-cm tumor in the pancreatic tail and in a 1-cm tumor in the pancreatic body. Serum glucagon levels were elevated to 54,405 pg/mL and a preoperative diagnosis of glucagonoma was made. The pancreatic tail and spleen were resected en bloc, along with a protruding tumor in the pancreatic body. However, histopathological evaluation revealed diffuse glucagonoma throughout the pancreas. When we retrospectively reviewed abdominal CE-CT after the operation, the entire pancreas was seen to be enlarged and diffusely enhanced by strong spots. Immunohistochemical examination using anti-CD31 demonstrated rich microvessels in two solid glucagonomas as well as microglucagonoma throughout the entire pancreas, indicating hypervascularity. Enlarged pancreas and diffuse enhancement of the pancreas by strong spots may be characteristic features of diffuse glucagonoma on abdominal CE-CT.

Dickson PV, Rich TA, Xing Y, et al.
Achieving eugastrinemia in MEN1 patients: both duodenal inspection and formal lymph node dissection are important.
Surgery. 2011; 150(6):1143-52 [PubMed]

BACKGROUND: Controversy exists regarding the role and extent of operation for patients with multiple endocrine neoplasia type 1 (MEN1) and hypergastrinemia.
METHODS: An institutional MEN1 database was reviewed to identify patients with evidence of hypergastrinemia. The relationship of extent of resection to achievement of eugastrinemia was evaluated.
RESULTS: Operation was performed in 20 patients with MEN1 and hypergastrinemia with a median follow-up of 71 months. Duodenal gastrinomas were identified in 85% of patients who underwent duodenal evaluation. Nodal metastases were identified in 80%. Patients who underwent anatomic regional lymph node dissection (RLND) had a median of 16 nodes removed, vs 1 in patients who did not undergo a formal regional lymphadenectomy. Eugastrinemia was achieved in 12 patients (60%), and 8 (40%) had persistent hypergastrinemia. Compared with patients with persistent hypergastrinemia, patients rendered eugastrinemic more often underwent duodenal evaluation (11/12 vs 2/8; P = .01) and RLND (11/12 vs 3/8; P = .03); there was no relationship between pancreatic resection and achievement of eugastrinemia (P = .32).
CONCLUSION: For patients with MEN1-associated hypergastrinemia selected for operative treatment, a strategy including duodenal evaluation and anatomic regional lymphadenectomy is associated with long-term eugastrinemia. In contrast, the extent of pancreatic resection should be dictated by the extent and distribution of pancreatic neuroendocrine neoplasms, rather than by the presence of hypergastrinemia.

Ekeblad S, Lejonklou MH, Stålberg P, Skogseid B
Prognostic relevance of survivin in pancreatic endocrine tumors.
World J Surg. 2012; 36(6):1411-8 [PubMed] Article available free on PMC after 01/09/2013

BACKGROUND: Better prognostic markers are needed for pancreatic endocrine tumors. Survivin is an apoptosis inhibitor that is suggested to have a negative prognostic impact in several tumor types. Contradictory data exist, especially regarding the significance of a nuclear versus cytoplasmic location of survivin. The prognostic relevance of nuclear and cytoplasmic survivin expression in pancreatic endocrine tumors-controlled for the tumor Ki-67 index, World Health Organization classification, and TNM stage-was investigated.
METHODS: A total of 111 patients treated at a tertiary referral center were retrospectively evaluated. Clinical data were gathered from medical records. Immunohistochemistry for survivin and Ki-67 was performed on paraffin-embedded tissue. Univariate and multivariate Cox analyses were performed.
RESULTS: Patients with tumors that had <5% survivin-positive nuclei had a mean survival of 225 months [95% confidence interval (CI) 168-281]. The corresponding figure for patients with 5 to 50% survivin-positive tumor cell nuclei was 101 months [95% CI 61-140; hazard ratio (HR) 2.4; P < 0.01) and with >50% survivin-positive nuclei 47 months (95% CI 24-71; HR 4.9; P < 0.001). Nuclear survivin expression in >50% of the tumor cells was an independent marker of a poor prognosis (HR 5.7; P < 0.01). Cytoplasmic survivin was not a significant prognostic factor in the multivariate analysis (HR 0.94; P = 0.90).
CONCLUSIONS: High expression of nuclear survivin is a significant marker of a poor prognosis in patients with a pancreatic endocrine tumor.

Tomita T
Immunocytochemical staining for islet amyloid polypeptide in pancreatic endocrine tumors.
Islets. 2011 Nov-Dec; 3(6):344-51 [PubMed] Article available free on PMC after 01/09/2013

AIMS/HYPOTHESIS: Islet amyloid polypeptide is originally identified as the chief constituent of amyloid in insulinomas and type 2 diabetic islets. This study aimed to identify islet amyloid polypeptide by immunocytochemical staining in pancreatic endocrine tumors including 30 cases of insulinomas and non-β-cell pancreatic endocrine tumors.
RESULTS: In normal islets, 62% of islet cells and 52% of insulin cells were granularly positive for insulin and IAPP, respectively, with more insulin positive cells than IAPP positive cells and some densely positive staining for insulin and IAPP in irregularly shaped a nuclear, degenerating islet β-cells. In pancreatic endocrine tumors, all 10 insulinomas were positive for islet amyloid polypeptide but 2 glucogonomas, 1 somatostatinoma, 6 of 7 pancreatic polypeptidomas, all 7 gastrinomas and all 3 non-functioning pancreatic endocrine tumors were negative for islet amyloid polypeptide whereas one pancreatic polypeptidoma was positive for islet amyloid polypeptide.
METHODS: Using commercially available rabbit anti-islet amyloid polypeptide antibody, immunocytochemical staining was performed on 30 cases of pancreatic endocrine tumors, consisting of 10 insulinomas, 2 glucagonomas, 1 somatostatinoma, 7 pancreatic polypeptidomas, 7 gastrinomas and 3 non-functioning pancreatic endocrine tumors. Pancreatic tissues containing pancreatic endocrine tumors were systematically immunostained for insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin and chromogranin A, in addition to islet amyloid polypeptide. When normal pancreatic tissues adjacent to pancreatic endocrine tumors were present, insulin, glucagon, somatostatin and islet amyloid polypeptide positive cells were counted for a total of 20 islets, which were divided into large islets and medium islets for each case.
CONCLUSIONS/INTERPRETATIONS: All 10 insulinomas and 1 pancreatic polypeptidoma were granularly positive for islet amyloid polypeptide, suggesting all 10 insulinomas contained enough insulin granules for IAPP whereas only one non-β-cell pancreatic endocrine tumor was co-localized with islet amyloid polypeptide in their secretary granules.

Williamson JM, Thorn CC, Spalding D, Williamson RC
Pancreatic and peripancreatic somatostatinomas.
Ann R Coll Surg Engl. 2011; 93(5):356-60 [PubMed] Article available free on PMC after 01/09/2013

BACKGROUND: Somatostatinomas are rare neuroendocrine tumours with an annual incidence of 1 in 40 million. They arise in the pancreas or periampullary duodenum. Most are clinically non-secretory and do not cause the somatostatinoma syndrome. Many are metastatic at presentation and their management is typically multimodal.
CASE HISTORIES: Four cases of somatostatinoma are described. Two patients with periampullary disease presented with biliary obstruction, one with frank jaundice and one with incidental bile duct obstruction on investigation of hepatitis B. Each patient had type 1 neurofibromatosis and resection of the somatostatinoma by means of a pylorus-preserving proximal pancreaticoduodenectomy has resulted in long-term survival. Another two patients with metastatic pancreatic somatostatinomas presented with abdominal pain. Contrasting management illustrates current treatment strategies that are dependent in part on the distribution of the disease.
DISCUSSION: The pathophysiology, presentation, clinical associations and role of diagnostic imaging are discussed for periampullary and pancreatic neuroendocrine tumours. Operative treatment has an important role in both the curative and palliative settings in conjunction with appropriate medical treatments and these are described. Management options depend on the extent of the disease and the cases are used to illustrate the rationale of such strategies.

Eguchi H, Tanemura M, Marubashi S, et al.
Arterial stimulation and venous sampling for glucagonomas of the pancreas.
Hepatogastroenterology. 2012 Jan-Feb; 59(113):276-9 [PubMed]

BACKGROUND/AIMS: Arterial stimulation and venous sampling (ASVS) is a catheter-based diagnostic technique used to identify the localization of an insulinoma or gastrinoma. The aim of this study was to clarify the clinical significance of ASVS for glucagonomas.
METHODOLOGY: Eight patients with pancreatic hypervascular tumors and elevated serum glucagon levels in the peripheral blood were enrolled. Pancreatic angiography was performed and a bolus dose of calcium was injected into a suitable artery. Hepatic venous blood samples were then obtained to measure concentrations of glucagon and insulin. All patients underwent surgical resection, and the resected specimens were investigated immunohistochemically.
RESULTS: Compared to insulin, the glucagon levels stabilized after calcium stimulation in four patients, with a 1.2-fold increase or decrease. In the remaining four patients, there was a 1.6- to 5.8-fold increase in glucagon levels. The peak value of glucagon was observed at 90s or 120s which was slower than the insulin peak observed in patients with insulinoma. The patients with elevated glucagon levels during ASVS exhibited positive immunostaining of glucagon in resected specimens.
CONCLUSIONS: Increase in glucagon after calcium stimulation was observed in patients with glucagonomas. ASVS for glucagonomas may be useful in determining the most suitable surgical procedure.

Shirai K, Inoue I, Kato J, et al.
A case of a giant glucagonoma with parathyroid hormone-related peptide secretion showing an inconsistent postsurgical endocrine status.
Intern Med. 2011; 50(16):1689-94 [PubMed]

A 53-year-old woman was admitted because of a giant pancreatic tumor. Hypercalcemia and a high serum parathyroid hormone-related peptide (PTHrP) level were observed. A hypoglycemic attack occurred during pancreatectomy, and the surgical specimen revealed a PTHrP-secreting glucagonoma. Liver metastases developed 1 and 5.5 years later, and bone metastases appeared 6 years after surgery. Her serum PTHrP concentrations remained normal after surgery, despite re-elevation of the serum glucagon concentration after recurrence. The clinical course of this case illustrates the process of development of neuroendocrine tumors secreting two or more hormones.