Hormonal tumor mapping for liver metastases of gastroenteropancreatic neuroendocrine neoplasms: a novel therapeutic strategy.

PURPOSE: In patients with metastatic functional gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), it is unknown what degree of tumor reduction is required to eliminate hormonal symptoms. We aimed to reduce hormonal symptoms derived from advanced GEP-NENs by efficient minimal intervention, constructing a hormonal tumor map of liver metastases. METHODS: Between 2013 and 2019, we treated 12 insulinoma or gastrinoma patients with liver metastases. Liver segments containing hormone-producing tumors were identified by injecting calcium gluconate via the hepatic arteries and monitoring the change in serum hormone concentration in the three hepatic veins. A greater-than-twofold increase in hormone concentration indicated a tumor-feeding vessel. RESULTS: Cases included eight insulinomas and four gastrinomas. Primary lesions were functional in three patients and nonfunctional in 9. Nine patients showed hormonal step-up indicating the presence of functional lesions; eight showed step-up in tumor-bearing liver segments, while one with synchronous liver metastases showed step-up only in the pancreatic region. Five patients underwent surgery. Serum hormone concentration decreased markedly after removing the culprit lesions in 3; immediate improvement in hormonal symptoms was achieved in all patients. Three patients with previous surgical treatment who showed step-up underwent transcatheter arterial embolization, achieving temporary improvement of hormonal symptoms. Four patients showed unclear localization of the hormone-producing tumors; treatment options were limited, resulting in poor outcomes. CONCLUSION: Hormonal tumor mapping demonstrated heterogeneity in hormone production among primary and metastatic tumors of GEP-NENs. Minimally invasive treatment based on hormonal mapping may be a viable alternative to conventional cytoreduction.

The Relationship of Gastrinoma in MEN 1 to Helicobacter pylori infection.

CONTEXT: Helicobacter pylori and Multiple Endocrine Neoplasia Type 1 (MEN 1) are risk factors for hypergastrinemia. Gastrin-secreting neoplasms of the foregut mucosa are both a source of, and potentially stimulated by, hypergastrinemia. OBJECTIVE: To determine the relationship between H pylori exposure and the prevalence and severity of hypergastrinemia in patients with MEN 1. DESIGN, SETTING & PATIENTS: Cross-sectional analysis of patients with a common MEN1 gene mutation managed at a tertiary referral hospital that underwent fasting serum gastrin and H pylori serum IgG measurement. INTERVENTION: H pylori IgG and serum gastrin concentration, determined via immunoassay. MAIN OUTCOME MEASURES: The prevalence and severity of hypergastrinemia and its relationship to past H pylori exposure. RESULTS: Thirty-four of 95 (36%) patients were H pylori IgG seropositive. H pylori seropositive patients were significantly more likely to exhibit hypergastrinemia compared with seronegative patients (relative risk [RR] 1.72, P = .023). H pylori exposure also predicted severe hypergastrinemia (RR 3.52, P = .026 and RR 9.37, P = .031 for patients with gastrin ≥ ×4 and ≥ ×8 the upper limit of normal [ULN], respectively). Gastrin concentrations ≥ ×10 ULN occurred exclusively in H pylori seropositive patients (0/61 vs 6/34, P = .001). Serum gastrin and alpha subunit were positively associated in H pylori-exposed (ß = 0.69, P = .001), but not in H pylori-unexposed patients. CONCLUSION: Past H pylori exposure was associated with increased prevalence and severity of hypergastrinemia in MEN 1 patients. Past H pylori-related hypergastrinemia may contribute to the pathogenesis of ongoing gastrin hypersecretion by susceptible foregut neuroendocrine tissues.

Diagnostic accuracy of selective arterial calcium injection test for localization of gastrinoma.

The appropriate localization of gastrinoma is still difficult. We aimed to evaluate the diagnostic accuracy of selective arterial calcium injection (SACI) for localization of gastrinomas including multiple lesions. This retrospective study included ten patients with surgically proven gastrinomas (gastrinoma group) and six patients without any findings suggesting Zollinger-Ellison syndrome (non-gastrinoma group). For SACI, calcium gluconate was injected into the arteries supplying pancreas, duodenum, and liver. Blood samples from the hepatic vein were obtained before and 30, 60, and 120 seconds after each injection. The results were considered positive when the increase in serum immunoreactive gastrin (IRG) levels within 60 seconds of calcium gluconate injection were more than 80 pg/mL and more than 20% from baseline. We evaluated the efficacy of SACI by comparing the SACI responses with definitive locations diagnosed by clinical and histopathological findings. In the gastrinoma group, false-positive responses were confirmed in seven of the ten patients. False-negative response was observed in one of the feeding arteries of one patient with gastrinomas in multiple locations. Conversely, the greatest increase in serum gastrin levels from baseline at 30 seconds indicated the true-positive responses in all patients with gastrinomas. In the non-gastrinoma group, calcium gluconate injection into gastroduodenal artery evoked positive responses in five of the six patients. In conclusion, our data suggest the strongest gastrin response evoked by SACI indicates the definitive location in patients with gastrinomas. In contrast, SACI could not accurately locate multiple gastrin-secreting lesions due to poor specificity.

Chromogranin A in gastrinomas: Promises and pitfalls.

Patients with neuroendocrine tumors are found with increasing frequency. Accordingly, knowledge about relevant tumor markers and assays for diagnosis and control has become essential. Neuroendocrine tumors release one or more granin proteins. Of these, chromogranin A (CgA) has so far become the most widely used general marker. The CgA protein is, however, extensively cleaved and otherwise modified during the biosynthetic processing. In addition, the CgA-processing in individual tumors varies considerably. But only few CgA-assays have taken the processing into account and characterized the assays with respect to precise epitope-specificity. Consequently, we do not know which fragments most CgA-assays measure. It is therefore at present difficult to compare CgA-measurements from tumor patients. Some tumors, however, release - in addition to granins - also a specific hormone that causes a clinical syndrome. This review uses gastrinomas (gastrin-producing tumors) as a starting point for discussion of CgA versus peptide hormone as tumor marker. Data available so far indicate that well-defined assays for gastrin have significantly higher diagnostic sensitivity than CgA measurements in gastrinomas. But the review suggests that CgA-quantitation using processing-independent analysis (PIA) may provide an equally high diagnostic sensitivity and in addition offer a simple possibility for estimation of the tumor-burden.

[Chromogranin A and neuroendocrine tumors]. / Cromogranina A y tumores neuroendocrinos.

Chromogranin A (CgA) is the most abundant granin in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). As a tumor marker is moderately sensitive and nonspecific. Despite the limitations of testing methods, which require careful interpretation, especially in the case of gastrinomas, patients treated with somatostatin analogues, and poorly differentiated tumors, it is the best tumor marker in GEP-NETs and may be of value in other tumors with neuroendocrine differentiation. CgA may be used as a marker in blood or tissue samples through immunohistochemical techniques. CgA levels correlate with tumor burden and extension and may be used for diagnosis and monitoring of GEP-NETs, especially midgut carcinoids and endocrine pancreatic tumors. It is also useful as a prognostic marker for detection of recurrence and monitoring of response to different treatments.

Criteria for the glucagon provocative test in the diagnosis of gastrinoma.

INTRODUCTION: The glucagon provocative test is useful for the diagnosis of gastrinoma. The aim of this study was to determine the criteria for the glucagon provocative test. METHODS: This study reviewed 8 patients that underwent the glucagon provocative test preoperatively and in whom the diagnosis was confirmed as gastrinoma histologically. The glucagon provocative test was performed by administering glucagon (20 µg/kg) intravenously, followed by 20 µg/kg h for the next 30 min, and plasma gastrin levels were measured 3 and 1 min before and 3, 5, 7, 10, 15, 20, and 30 min after the administration of glucagon. This study evaluated the peak value of plasma gastrin and the time required to reach the peak. RESULTS: Two of the 8 patients had multiple endocrine neoplasm type 1. The basal plasma gastrin levels ranged from 524 to 10,300 pg/ml. The time required to reach the peak was 3-10 min for all patients. The increase in the peak from the basal value was 235-8,920 pg/ml, and the percentage of increase was 38-337 %. CONCLUSIONS: These results suggest that a diagnosis of gastrinoma should thus be made when plasma gastrin levels peak within 10 min after glucagon administration, with an increase of greater than 200 pg/ml and greater than 35 % of the basal value.

Achieving eugastrinemia in MEN1 patients: both duodenal inspection and formal lymph node dissection are important.

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.

A rare case of renal gastrinoma.

We present a rare case of renal gastrinoma. To the best of our knowledge, only one case of renal gastrinoma has been reported in the literature so far. An African American male was diagnosed with Zollinger Ellison syndrome at the age of 15 years, when he underwent surgery for peritonitis secondary to duodenal ulcer perforation. Further evaluation was deferred and proton pump inhibitors were prescribed. Later evaluation showed a left renal mass. Serum gastrin levels were 4,307 pg/ml. A CAT scan of the abdomen showed 4- x 4-cm heterogeneous solid mass in the interpolar region of the left kidney with central hypodensity. Somatostatin scintigraphy confirmed a receptor-positive mass in the same location. Nephrectomy was done and the tumor was diagnosed on histopathological examination as a gastrinoma. At 6-month follow-up, gastrin levels were 72 pg/ml. After a follow-up of 6 years, the patient has no recurrent symptoms.

Duodenal gastrinoma: a diagnostic dilemma.

Preoperative assessment and localization is crucial in the management and outcome of patients with duodenal gastrinoma. Localization can be challenging because of small size and variable location. We describe our experience of managing 1 such patient by localizing the lesion during the preoperative period. Side-viewing endoscopy, endoscopic ultrasound, and somatostatin receptor scintigraphy determined the exact location of the tumor, which was confirmed during surgery on palpation, endoscopic transillumination, and duodenotomy. Antrectomy was performed, and the patient was asymptomatic after 8 months of follow-up and did not require antisecretory medications. His serum gastrin levels returned to normal during the postoperative period.

Curative resection of primary hepatic gastrinoma.

Primary hepatic gastrinoma is very rare, with fewer than 20 cases reported. We describe a 44-year-old woman in whom primary hepatic gastrinoma was strongly suspected clinically. The patient was referred to our hospital because of intractable diarrhea. She had elevated serum levels of alanine aminotransferase, aspartate aminotransferase, and fasting gastrin. A calcium provocative test showed a marked elevated serum gastrin level (17,000 pg/ml). Abdominal ultrasonography, computed tomography, and magnetic resonance imaging revealed a tumor in the right lobe of the liver, measuring 38 x 33 mm. No other tumor was detected in the pancreas, duodenum, or local lymph nodes on preoperative radiological imaging or endoscopic ultrasonography. The hepatic tumor was resected. Total intraoperative ultra-sonography and intraoperative exploratory palpation of the duodenum, pancreas, and lymph nodes showed no evidence of an extrahepatic tumor. Pathological findings and immunohistochemical studies revealed a neuroendocrine tumor with increased production of gastrin. Postoperatively, the serum gastrin level returned to normal.

Diagnosis and differential diagnosis of hypergastrinemia.

The most frequent conditions of hypergastrinemia in man are the Zollinger-Ellison syndrome with autonomous gastrin hypersecretion by the tumour cell and reactive hypergastrinemia in type A autoimmune chronic atrophic gastritis with achlorhydria causing unrestrained gastrin release from the gastrin-producing antral G-cells. Both entities differ with respect to the pH in the gastric fluid, which is < 2 in patients with Zollinger-Ellison syndrome and neutral in type A gastritis. Other conditions with moderate hypergastrinemia as treatment with proton pump inhibitors, gastric outlet obstruction, previous vagotomy, chronic renal failure or short bowel syndrome are of minor clinical importance.

Diagnosis and treatment of gastric neuroendocrine tumours.

Gastric neuroendocrine tumours (NET) are rare. Clinically they are classified in tumours type 1 to 3. The histological classification is according to the WHO 2000 classification for endocrine tumours. NET type 1 occur in coincidence with chronic atrophic gastritis, as single or multiple small tumours. The prognosis of type 1 tumours is excellent, with no tumour related death reported during follow-up. NET type 2 are part of the MEN-1 syndrome. These tumours may be more aggressive and even develop metastasis. However, in most patients with MEN-1 the prognosis is due to other manifestations of the disease as duodenal or pancreatic neuroendocrine tumours. Gastric neuroendocrine tumours type 3 are sporadic tumours without relationship to other gastric pathology. They tend to occur earlier, without sex preference. These tumours may develop an aggressive course, with metastatic disease and an overall poor prognosis. Thus, aggressive surgical therapy is recommended.

Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors.

The Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic background of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH > 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specificity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO > 0.6 is highly specific for gastrinoma. To localize the gastrin-secreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors in up to 2-3-fold increased standard doses to inhibit gastric acid hypersecretion. Elevation of gastric pH > 4 will be the therapeutic target to protect the mucosa of the upper gastrointestinal tract. Basal acid output should be reduced to less than 10 mEq H(+) per hour which requires administration of highly potent proton pump inhibitors with a recommended starting dose of 60 mg omeprazole equivalents per day.

Localisation and staging of gastrin producing tumours using cross-sectional imaging modalities.

Cross sectional imaging in the assessment of gastrinomas has three major applications: Tumor localization (sporadic gastrinoma, MEN I) in patients undergoing primary or secondary surgery. Staging of metastasized tumors, especially assessment of lymph nodes and liver metastases, possibly including a risk analysis prior to liver resection. Post-surgery follow-up and monitoring of bio- or chemotherapy. Detection of primary tumors is strongly correlated with their size. However, the sensitivity of surgical assessment of the mostly small tumors by experienced surgeons is much higher than that of any imaging modality. Of all imaging modalities, endoultrasonography (EUS) followed by Somatostatin receptor scintigraphy (SRS) is the most sensitive modality for the assessment of pancreatic tumors in asymptomatic patients suffering from a MEN-I syndrome. Scintigraphy has the highest sensitivity in tumors of symptomatic patients and in the assessment of metastases. CT and MRI are only second line diagnostic modalities. Their sensitivity is largely dependent on the selection of patients. As a potential application, 3D reconstruction of nearly isotropic CT data sets for the risk assessment prior to liver resection is currently developing. Due to the absent radiation exposure, MRI is increasingly utilized to monitor the response of metastases under systemic therapy, e.g. in clinical trials.

Imaging of gastrinomas by nuclear medicine methods.

Somatostatin receptor scintigraphy (SRS) is a valuable method for the detection of somatostatin receptor-positive lesions. Most gastrinomas (over-)express the somatostatin receptor subtype 2 which can be targeted by In-111 labeled Octreotide. Different studies show a high sensitivity of SRS for the localization and staging of gastrinomas. SRS seems to be superior to other non-invasive imaging modalities and has been proven to significantly contribute to patient management. However, the sensitivity depends on the size and exact localization of the tumors. Smaller lesions and lesions located in the duodenum show a significantly lower sensitivity. In any case, SRS belongs to the routine imaging procedure for gastrinomas for localization and staging and can also be used for evaluation of the tumor progression.

Surgical aspects of gastrinoma in multiple endocrine neoplasia type 1.

Gastrinoma is the most frequent functional pancreaticoduodenal endocrine tumor in patients with multiple endocrine neoplasia type 1 (MEN1) and one major determinant of mortality in this syndrome. Whether routine surgical exploration should be performed in a patient with MEN1 associated Zollinger-Ellison syndrome (ZES) to possibly reduce the malignant spread and eventually increase survival still remains controversial. There is not only disagreement about the indication for surgical exploration, but also what type of procedure should be performed, since sufficient evidence-based data are not available. The article discusses the available data on treatment strategies of MEN1 associated ZES.

Surgical treatment of sporadic gastrinoma.

Surgical therapy for sporadic gastrinoma profits from innovative pre- and intraoperative diagnostics. Preoperative gastrinoma localization is enhanced by sophisticated endoscopic ultrasonography, scintigraphic and arteriographic studies with hormone sampling. Thereby a concise surgical approach is guided and additional intraoperative control of success may be gained by endoscopic transillumination and measurement of stimulated gastrin levels.

Medical treatment of gastrinomas.

Gastrinomas are functional neuroendocrine tumors of the gastroenteropancreatic system. Surgery is first line treatment in gastrinomas, however often fails to be curative. This manuscript reviews current strategies of medical treatment of surgically non-curable gastrinoma. Symptomatic treatment with H(+)-K(+)-ATPase proton-pump inhibitors suppresses hypersecretion of gastric acid and substantially improves quality of life in patients with Zollinger-Ellison syndrome. Further medical therapy is only recommended in cases of progressive metastatic gastrinoma. In well differentiated neuroendocrine carcinoma (G1 and G2) a so-called biotherapy with somatostatin analogues exists as first-line and chemotherapy with streptocotozin plus doxorubicine/5-FU as second-line medical treatment option. In poorly differentiated neuroendocrine carcinoma (G3) chemotherapy with etoposide plus cisplatin is possible. Prospective future therapeutic strategies may include treatment with novel somatostatin analogues as well as angiogenesis inhibitors and kinase inhibitors targeting tumor-specific signaling cascades.