Recurrence after surgical resection of nonmetastatic sporadic gastrinoma: Which prognostic factors and surgical procedure?

BACKGROUND: The only curative treatment of gastrinoma is complete resection, but its surgical management remains controversial and prognostic factors of sporadic nonmetastatic gastrinoma are poorly known. METHODS: This was a retrospective study including all patients who underwent elective surgery for nonmetastatic sporadic gastrinoma between 2000 and 2020 in 15 hospitals. The primary and secondary outcomes were overall survival and disease-free survival predictive factors. RESULTS: In total, 108 patients were included, of which 68 (63%) were duodenal, 19 (18%) pancreatic, and 21 (19%) primary lymph node gastrinomas, with no major difference in clinical presentation. Among the 68 duodenal gastrinomas, 26% (n = 18) underwent pancreaticoduodenectomy (PD) and 74% (n = 50) underwent duodenotomy with the excision of duodenal wall tumors and lymphadenectomy (DUODX + LN). Overall, the median overall survival was 173 months, and the 5-year overall survival was 94%, with no predictive factors identified. The median disease-free survival was 93 months, and the 5-year disease-free survival was 63%. Tumor size >2 cm (P = .00001), grade (P = .00001), and pancreatic tumor location (P = .0001) were predictive factors of recurrence; however, in multivariate analysis, only tumor size >2 cm (P = .005) and grade (P = .013) were independent predictors of recurrence. Age, sex, preoperative gastrin level, lymphadenectomy <10 resected lymph nodes, and metastatic lymph nodes on surgical specimens were not predictors of recurrence. For duodenal gastrinomas, surgical procedures (PD versus DUODX + LN) did not have a significant effect on overall survival and disease-free survival. CONCLUSION: Sporadic nonmetastatic gastrinomas had an excellent overall survival. Recurrence is frequent and influenced by tumor size and grade. Regarding sporadic duodenal gastrinoma, duodenotomy with excision of duodenal wall tumors with lymphadenectomy could be considered a valid surgical option, in the absence of clear oncologic superiority of PD.

Ectopic Cushing syndrome: Report of 9 cases. / Síndrome de Cushing ectópico: descripción de 9 casos.

INTRODUCTION: Ectopic Cushing's syndrome (ECS) is a rare condition caused by ACTH secretion by extrapituitary tumors. Its low frequency makes it difficult to acquire experience in its management. The aim of this study was to describe patients with ECS seen at the endocrinology department of a tertiary hospital over 15 years. METHODS: This was a retrospective study of the clinical, biochemical and radiographic data, treatment, and course of patients with ECS seen from 2000 to 2015. RESULTS: Nine patients (6 of them female) with a mean age of 47 years were included in the study. The clinical syndrome developed in less than 3 months in all cases but one, and most patients also had edema, hyperpigmentation and/or hypokalemia. Mean urinary free cortisol and ACTH levels were 2,840µg/24h and 204pg/mL respectively. The ectopic origin was confirmed by a combination of dynamic non-invasive tests and radiographic studies in most cases. The tumor responsible could be identified in 8 cases, and 7 patients had metastatic dissemination. Primary treatment was surgery in one patient, surgery combined with systemic therapy in 3, and chemotherapy in the other 3 patients. Bilateral adrenalectomy was required in 4 patients to control hypercortisolism. After a mean follow-up of 40 months, 3 patients died, 5 were still alive, and one had been lost to follow-up. CONCLUSIONS: Our study confirms that ECS covers a wide spectrum of tumors of different aggressiveness and nature. The ectopic origin of Cushing's syndrome can usually, be suspected and confirmed in most cases without the need for invasive tests. Control of both hypercortisolism and the tumor requires multiple treatment modalities, and multidisciplinary management is recommended.

Metastatic gastrinoma in the breast mimicking primary solid papillary carcinoma.

We report a case of metastatic gastrinoma to the breast morphologically mimicking solid papillary carcinoma of the breast. A 59-year-old woman presented with a hypoechoic right breast mass that histologically revealed solid nests of small monotonous tumor cells, fibrovascular cores, and round to oval nuclei with fine chromatin and small nucleoli. Immunohistochemistry demonstrated chromogranin and synaptophysin positivity. Tumor prognostic markers showed weak positivity for estrogen receptor and negativity for progesterone receptor. Although an initial diagnosis of solid papillary carcinoma was rendered, subsequent identification of the patient's clinical history of pancreatic gastrinoma and an additional immunohistochemical stain for gastrin supported a diagnosis of metastatic gastrinoma. We report this rare case to increase awareness of metastatic neuroendocrine tumors in the breast. Multiple breast lesions and lack of expression of estrogen/progesterone hormone receptors should prompt careful review of the patient's clinical history to rule out metastatic neuroendocrine disease.

An esophageal gastrointestinal stromal tumor in a patient with MEN1-related pancreatic gastrinoma: an unusual association and review of the literature.

Both multiple endocrine neoplasia type 1 (MEN1)-related gastrinomas and gastrointestinal stromal tumors (GISTs) are rare neoplasms, and their association has been rarely reported. We describe an unusual association between a GIST and a MEN1-related gastrinoma. A 44-year-old man had undergone surgical removal of a pancreatic gastrinoma in 2004 and was then administered long-term somatostatin analogs, and diagnosed as having MEN1 syndrome. Following an uneventful follow-up, in April 2009, an upper gastrointestinal tract endoscopy showed esophageal narrowing, with evidence of a 2-cm solid mass on endoscopic ultrasonography. Histology revealed a tumor composed of elongated cells with plump cytoplasm arranged in a storiform pattern. The immunophenotype of the lesion was CD117 and Platelet Derived Growth Factor (PDGF) positive, whereas alpha-1 muscle actin and S-100 protein were negative. Due to morphological and immunohistochemical results, a final diagnosis of esophageal GIST was made. The association between GISTs and MEN1 could be casual, although a single case of the coexistence of a GIST and a MEN1-related gastrinoma has already been reported. A role of the MEN1 gene in the pathogenesis of GISTs could be hypothesized.

Gastrinoma and neurofibromatosis type 2: the first case report and review of the literature.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors have occasionally been described in association with neurofibromatosis type 1, whereas an association with neurofibromatosis type 2 has never been reported. CASE PRESENTATION: This report refers to an Italian 69 year old woman with neurofibromatosis type 2 and a pancreatic gastrinoma. In the past she had encephalic meningiomas, a tongue schwannoma and bilateral acoustic neurinomas. She presented with weight loss and a long-term history of diarrhea, responsive to proton pump inhibitors. Upper gastrointestinal endoscopy revealed peptic ulcer of the duodenal bulb. Blood tests were normal, except for the elevation of plasma gastrin (1031 pg/ml; reference value <108) and chromogranin A (337 U/L; reference value <36). After secretin stimulation testing, the plasma gastrin level rose to 3789 pg/ml. The abdomen magnetic resonance imaging and gallium68-DOTATOC positron emission tomography scan demonstrated the presence of a 1.2 x 2 cm lesion in the pancreatic head and a liver metastatis. Pancreatic endoscopic ultrasound with fine needle aspiration revealed cytomorphologic features suggestive of pancreatic gastrinoma. Brain magnetic resonance showed a pituitary microadenoma. There was no evidence of hyperparathyroidism. The genetic test for multiple endocrine neoplasia type 1 syndrome mutation was negative. CONCLUSION: This report focuses on the first case of coexistence of gastrinoma with neurofibromatosis type 2. Although the clinical relevance of this association remains to be determined, our case report will surely give cause for due consideration.

Metastatic gastrinoma in a pediatric patient with Zollinger-Ellison syndrome.

Metastatic neuroendocrine tumors of childhood are extremely rare, and as such present diagnostic and therapeutic challenges. Here, we report a case of gastrinoma with extensive hepatic metastases in a pediatric patient with Zollinger-Ellison Syndrome who underwent orthotopic liver transplant followed by cytotoxic chemotherapy, somatostatin analog therapy, and immune modulation.

Zollinger-Ellison syndrome: recent advances and controversies.

PURPOSE OF REVIEW: To review the recent advances and current controversies in patients with Zollinger-Ellison syndrome (ZES). RECENT FINDINGS: Recent advances in the management of ZES include: improved understanding of the pathogenesis of gastrinoma and pancreatic neuroendocrine tumors, new prognostic classification systems, new diagnostic algorithms, more sensitive localization studies, new treatment strategies including improved control of gastric acid secretion and role for surgery, and new approaches to patients with advanced disease. Controversies include: the best approach to a patient with hypergastrinemia suspected of possibly having ZES, the appropriate gastrin assay to use, the role of surgery in patients with ZES, especially those with multiple endocrine neoplasia type 1, and the precise order of therapeutic modalities in the treatment of patients with advanced disease. SUMMARY: This review updates clinicians regarding important advances and controversies required to optimally diagnose and manage patients with ZES.

Surgery for metastatic neuroendocrine tumors with occult primaries.

INTRODUCTION: Neuroendocrine tumors (NETs) frequently metastasize prior to diagnosis. Although metastases are often identifiable on conventional imaging studies, primary tumors, particularly those in the midgut, are frequently difficult to localize preoperatively. MATERIALS AND METHODS: Patients with metastatic NETs with intact primaries were identified. Clinical and pathologic data were extracted from medical records. Primary tumors were classified as localized or occult based on preoperative imaging. The sensitivities and specificities of preoperative imaging modalities for identifying the primary tumors were calculated. Patient characteristics, tumor features, and survival in localized and occult cases were compared. RESULTS: Sixty-one patients with an intact primary tumor and metastatic disease were identified. In 28 of these patients (46%), the primary tumor could not be localized preoperatively. A median of three different preoperative imaging studies were utilized. Patients with occult primaries were more likely to have a delay (>6 mo) in surgical referral from time of onset of symptoms (57% versus 27%, P = 0.02). Among the 28 patients with occult primary tumors, 18 (64%) were found to have radiographic evidence of mesenteric lymphadenopathy corresponding, in all but one case, to a small bowel primary. In all but three patients (89%), the primary tumor could be identified intraoperatively. CONCLUSION: The primary tumor can be identified intraoperatively in a majority of patients with metastatic NETs, irrespective of preoperative localization status. Referral for surgical management should not, therefore, be influenced by the inability to localize the primary tumor.

Lymph nodes metastasis and recurrences justify an aggressive treatment of gastrinoma.

In the current study, short- and long-term outcomes after aggressive surgical treatment for gastrinoma were evaluated. From August 1990 to August 2009, 20 patients diagnosed with Zollinger Ellison syndrome were reviewed. Eleven pancreaticoduodenectomies, three total pancreatectomies, four lymph node dissections, four enucleations and two palliative procedures were performed. Four (27.8 %) patients had disease associated with MEN1 syndrome, 13 (72.2 %) had sporadic gastrinomas (SG) and 3 had disease of unknown primary origin. No in-hospital mortality was observed. After radical resection, lymph node metastasis was present in 82 % of the cases. Eight percent of patients who underwent radical resection developed recurrence compared with 100 % of those who underwent enucleoresection (p = 0.03). Average time to recurrence in patients with sporadic gastrinoma was 66.7 months (confidence interval (CI) 62.9-70.5) in those treated with enucloeresection compared to 181.1 months (CI 124.3-237.8) in the radical resection group (p = 0.007). One recurrence was observed in the MEN1 group. Based on post-operative mortality, recurrence and lymph node metastasis, our data suggest that patients with gastrinoma should undergo abdominal exploration with aggressive resection of the primary tumour and regional lymph nodes in place of conservative treatment.

Surgical treatment of gastrinomas: a single-centre experience.

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.

[PPI-sensitive diarrhea - unusual case of an adolescent with sporadic gastrinoma]. / Ansprechen einer episodenhaften chronischen Diarrhoe auf Protonenpumpenhemmer. Seltener Fall eines Jugendlichen mit sporadischem Gastrinom.

HISTORY AND CLINICAL FINDINGS: A 14-year-old boy was admitted to hospital because of chronic episodic diarrhea lasting for 4 years. Previous investigations in the past had not revealed the cause of the symptoms. INVESTIGATIONS: The 13C-triglyceride breathing test showed a diminished intestinal lipolysis. Endoscopic examination demonstrated small gastroduodenic ulcers. During therapy with proton-pump inhibitors the diarrhea stopped. DIAGNOSIS, TREATMENT AND COURSE: The combination of gastroduodenic ulcers and improvement of diarrhea with PPI-therapy were suggestive of Zollinger-Ellison syndrome. Endosonography and MR-scan showed an extrapancreatic mass with marked activity during somatostatin receptor scintigraphy. The primary tumor was excised, a liver metastasis was treated with radiofrequency ablation. The histological examination confirmed the diagnosis of a gastrinoma. CONCLUSION: In patients with chronic diarrhea, especially if the symptoms are PPI-sensitive, a gastrinoma should be considered.

Portal vein embolization using a Histoacryl/Lipiodol mixture before right liver resection.

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.

Recurrence after surgical resection of gastrinoma: who, when, where and why?

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.

Analysis of lymph node metastasis in pancreatic neuroendocrine tumors (PNETs) based on the tumor size and hormonal production.

BACKGROUND: Because of the rarity and variety of pancreatic neuroendocrine tumors (PNETs), there have been few reports regarding the indication for lymph node dissection in patients with these tumors. This study aimed to evaluate the risk of lymph node metastasis of PNETs based on the tumor size and hormonal production. METHODS: Data for a total of 66 patients who had PNETs resected at our department between 1987 and 2010 were retrospectively studied. The clinicopathological features, including the disease-specific survival rate, were assessed based on the status of lymph node metastasis at the time of initial surgical resection. Then the cut-off point of tumor size to predict lymph node metastasis was estimated. RESULTS: There were 12 patients (18%) with lymph node metastasis. The frequency of lymph node metastasis tended to be higher in gastrinomas than that in other tumors (43 vs. 15%; P = 0.08). The size of PNETs with lymph node metastasis was significantly larger than that of the PNETs without metastasis (P = 0.04). The postoperative survival rate in the PNET patients with lymph node metastasis was significantly lower than that in the patients without metastasis (P < 0.0001). Only 2 (8%) of 26 PNETs with a tumor size of <15 mm had lymph node metastasis, and both of these were gastrinomas. On the other hand, 10 (25%) of the remaining 40 PNETs with a tumor size of ≥15 mm had lymph node metastasis. Notably, there were no PNETs with lymph node metastasis in 22 non-gastrinomas with a tumor size of <15 mm. CONCLUSIONS: Non-gastrinomas with a tumor size of ≥15 mm and all gastrinomas would be an indication for pancreatectomy with lymph node dissection.

Safety of hepatic resection in metastatic disease to the liver after yttrium-90 therapy.

BACKGROUND: Unresectable hepatic metastases from aerodigestive cancers are common and in most cases herald a poor prognosis. A small percentage of patients maybe amenable to surgical resection or ablation once the biology of the disease and the burden of hepatic disease are better understood. The use of hepatic arterial resin microspheres containing the ß emitter, yttrium-90, has been reported in the treatment of unresectable hepatic metastases. The goal of this review was to evaluate the use of yttrium-90 hepatic arterial therapy in the management of hepatic metastases and surgical downstaging. METHODS: We reviewed our prospective hepatic arterial therapy registry and found 44 patients who had received Sir Sphere treatment for unresectable hepatic malignancies from 11/06 to 7/08. Response was assessed by using CT-imaging and characterized using modified response evaluation criteria in solid tumors (RECIST). All patients were managed in a multidisciplinary tertiary referral center specializing in hepatic malignancies. RESULTS: A total of 44 patients, 34 men and 10 women, with a median age of 60 y (range 44-8), received 67 treatments. The disease types treated were one adenosquamous tongue, one adrenal, nine carcinoid, three cholangiocarcinoma, four esophageal, one gastric, one gastrinoma, one GIST, four HCC, 15 colorectal, one melanoma, one non-small-cell lung, one occular, and one sarcoma. Four patients treated proceeded to resection because of downstaging of disease or no evidence of extrahepatic progression. The median age in these patients was 61 y (range 49-62). All of the patients had less than 25% tumor burden in the liver. Surgical therapy consisted of two patients undergoing right hepatic lobectomy, one patient who also underwent two wedge resections of segment 3, and one patient who had a left lateral hepatectomy with right lobe microwave ablation. The median length of postoperative stay was 7 d. There was no evidence of liver dysfunction following resection in any of the patients. None of the patients show evidence of recurrence in the liver following resection. One patient has had progression of disease in the lungs following resection, histologically confirmed as metastatic rectal carcinoma. All of the patients are currently alive with a median survival of 2 y. CONCLUSION: Hepatic directed yttrium-90 is a minimally invasive, highly effective therapy that can be utilized to downstage the hepatic burden and/or assess the biology of the disease to allow for appropriate treatment. The use of yttrium-90 microspheres for radio-embolization of metastases in the liver can successfully downstage the lesions to allow for surgical resection in patients with amenable predictors, and can provide a significantly better prognosis in these patients. This form of therapy for the purposes of downstaging tumors for resection merits more extensive study in order to provide the best possible outcomes for patients with metastatic liver disease.

Percutaneous radiofrequency ablation approach through the spleen: initial case report for pancreatic tail gastrinoma.

Gastrinoma has a low incidence, and the pancreas-originated gastrinoma is rare. Pancreatic gastrinoma patients with liver metastases have poor prognosis and short survival. Local treatment to reduce the tumor burden helps to improve symptoms and slows down tumor progression for patients with unresectable tumors. We report a case of pancreatic tail gastrinoma with unresectable liver metastases. The patient received a comprehensive minimally invasive interventional treatment, that is, chemoembolization and radiofrequency ablation for liver metastases, and percutaneous transplenic radiofrequency ablation combined with radioactive 125I seed implantation for pancreatic tail gastrinoma. The patient was followed up for more than 20 months, and showed no clear evidence of tumor recurrence. We explored the safety and feasibility of percutaneous transplenic radiofrequency ablation for unresectable pancreatic tail gastrinoma. This transplenic approach allow more indications for minimally invasive therapy and provides a new treatment option not only for patients with unresectable pancreatic tail tumor but also for patients refusing surgery.