Xenon-inhalation computed tomography for noninvasive quantitative measurement of tissue blood flow in pancreatic tumor.

BACKGROUND AND AIMS: The purpose of this prospective study was to demonstrate the ability to measure pancreatic tumor tissue blood flow (TBF) with a noninvasive method using xenon inhalation computed tomography (xenon-CT) and to correlate TBF with histological features, particularly microvascular density (MVD). METHODS: TBFs of pancreatic tumors in 14 consecutive patients were measured by means of xenon-CT at diagnosis and following therapy. Serial abdominal CT scans were obtained before and after inhalation of nonradioactive xenon gas. TBF was calculated using the Fick principle. Furthermore, intratumoral microvessels were stained with anti-CD34 monoclonal antibodies before being quantified by light microscopy (×200). We evaluated MVD based on CD34 expression and correlated it with TBF. RESULTS: The quantitative TBF of pancreatic tumors measured by xenon CT ranged from 22.3 to 111.4 ml/min/100 g (mean ± SD, 59.6 ± 43.9 ml/min/100 g). High correlation (r = 0.885, P < 0.001) was observed between TBF and intratumoral MVD. CONCLUSION: Xenon-CT is feasible in patients with pancreatic tumors and is able to accurately estimate MVD noninvasively.

First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas.

BACKGROUND: Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In vitro data indicate that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines. The authors retrospectively evaluated the efficacy of capecitabine and temozolomide in 30 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS), and overall survival (OS). METHODS: Patients with metastatic, well, or moderately differentiated pancreatic endocrine carcinomas who had not received prior systemic chemotherapy were treated with capecitabine (750 mg/m² twice daily, days 1-14) and temozolomide (200 mg/m² once daily, days 10-14) every 28 days. RESULTS: Among 30 patients treated, 21 (70%) patients achieved an objective radiographic response. Median progression-free survival was 18 months. The rate of survival at two years was 92%. Only 4 patients (12%) experienced grade 3 or 4 adverse events. CONCLUSIONS: The combination of capecitabine and temozolomide is associated with an exceptionally high and durable response rate in metastatic endocrine carcinomas of the pancreas. Clinical endpoints, including response rate, survival, and toxicity, are superior to those observed with streptozocin-based regimens.

Usefulness of EUS combined with contrast-enhancement in the differential diagnosis of malignant versus benign and preoperative localization of pancreatic endocrine tumors.

BACKGROUND: Pancreatic endocrine tumors (PETs) develop in relatively few patients, but they are often difficult to diagnose because of their small size and various clinical symptoms. OBJECTIVE: The aim of this study was to investigate the usefulness of EUS combined with contrast enhancement (CE-EUS) in the preoperative localization of PETs and the differentiation between malignant and benign PETs. DESIGN AND SETTING: Single-center retrospective study. PATIENTS: Sixty-two pathologically certified PETs of 41 patients who underwent EUS, multiphasic multidetector computed tomography (MDCT), and transabdominal US at our institute since 2001. INTERVENTIONS: Intravenous injection of US contrast media. MAIN OUTCOME MEASUREMENTS: Comparison of EUS, MDCT, and US in the preoperative identification of PETs, and the characteristic findings of EUS with malignancy. RESULTS: EUS showed high sensitivity (95.1%) in identifying PETs compared with MDCT (80.6%) and US (45.2%). Multivariable logistic regression analysis showed that heterogeneous ultrasonographic texture was the most significant factor for malignancy (OR = 53.33; 95% CI, 10.79-263.58). Most heterogeneous hypoechoic areas and anechoic areas corresponded to hemorrhage or necrosis on pathologic examination. They were identified as filling defects in CE-EUS and were more clearly recognized than in conventional EUS. LIMITATIONS: Retrospective study. CONCLUSION: EUS has higher sensitivity in preoperative localization of PETs compared with MDCT and US. The characteristics of EUS and CE-EUS findings in malignant PETs were clarified, and they will improve the diagnostic accuracy of PETs.

EUS-FNA predicts 5-year survival in pancreatic endocrine tumors.

BACKGROUND: Pancreatic endocrine tumors (PETs) differ in clinical behavior and prognosis. Determination of malignant potential through specimens obtained by EUS-FNA can help in the management of these patients. OBJECTIVE: To determine the value of EUS-FNA for diagnosing PETs and for classifying their underlying malignant potential based on the World Health Organization (WHO) classification. DESIGN: Single-center, retrospective, cohort study. SETTING: Tertiary referral hospital. PATIENTS: This study involved 86 consecutive patients (44 men, mean age 58 +/- 14 years) who had been diagnosed with PETs and submitted to EUS-FNA from January 1999 to August 2008. INTERVENTION: EUS-FNA of a pancreatic mass and/or a metastasis site. Immunohistochemistry on microbiopsies or on monolayer cytology was routinely used. The lesions were classified as recommended by the WHO. MAIN OUTCOME MEASUREMENTS: EUS-FNA sensitivity and 5-year survival rate. RESULTS: Overall, in 90% (77 of 86) of patients in this study, PET was diagnosed with EUS-FNA. The sensitivity did not vary with tumor size, type, location, or the presence of hormonal secretion. Of 86 patients, 30 (35%) were submitted to surgical resection. The kappa correlation index between the WHO classification obtained by EUS-FNA and by surgery was 0.38 (P = .003). Major discrepancies were found in the group of patients diagnosed with endocrine tumor of uncertain behavior by EUS-FNA, because 72% turned out to have well-differentiated endocrine carcinoma. Sixteen patients (27%) died during a mean follow-up period of 34 +/- 27 months. The 5-year survival rates were 100% for endocrine tumors, 68% for well-differentiated endocrine carcinomas, and 30% for poorly differentiated endocrine carcinomas (P = .008, log-rank test). LIMITATIONS: Retrospective design, selection bias, and small sample size. CONCLUSIONS: This largest single-center experience to date demonstrated the accuracy of EUS-FNA in diagnosing and determining the malignant behavior of PETs. EUS-FNA findings predict 5-year survival in patients with PETs.

Pancreatic endocrine tumor EUS-guided FNA DNA microsatellite loss and mortality.

BACKGROUND: The clinical course of pancreatic endocrine tumors (PET) depends on tumor size, the presence of invasion or metastasis, the Ki-67 index, mitoses per high power field, and mutational damage. Most of this information is not available before surgery for clinical decision making or prognostication. OBJECTIVE: To evaluate PET EUS-guided FNA (EUS-FNA) microsatellite loss analysis in the context of PET-related mortality. DESIGN: A single institution retrospective cohort. PATIENTS: Patients with PET diagnosed by EUS-FNA who underwent DNA microsatellite loss analysis and at least 1 year of follow-up or subsequent death. INTERVENTION: PET microsatellite loss analysis results and current clinical status were compared. RESULTS: Twenty-nine patients were included in the final analysis; the mean age of the patients was 57 years, and 10 were women (35%). The mean follow-up was 33.7 months (median 30 months, range 2-66 months). Twelve patients had disease progression, and 8 died, all from disease-specific causes. Malignant PET contained multiple microsatellite losses, with a median fractional allelic loss (FAL) of 0.37 (range 0.12-0.69, interquartile range [IQR] 0.23-0.42), significantly different from benign PET, median FAL 0 (range 0-0.18, IQR 0-0.08, P < .0001). Survival analysis revealed a significant difference in disease recurrence or progression at 2 years (P < .0001) and in the 5-year survival between patients with FAL 0.2 (P < .0001). Logistic regression could not be performed because of the perfect association between an FAL >0.2 and disease status or mortality. LIMITATIONS: Retrospective design, referral bias, and DNA analysis availability. CONCLUSIONS: PET EUS-FNA microsatellite loss analysis provides preoperative prognostic information. An FAL >0.2 is not only associated with disease progression but also with mortality.

[A long-term survival case of unresectable malignant pancreatic endocrine tumor successfully treated with systemic chemotherapy].

A 55-year-old man was admitted to our hospital because of high grade fever in October 1999. Computed tomography showed a solid tumor in the tail of the pancreas with multiple liver tumors. We diagnosed him as unresectable pancreatic tail cancer with multiple liver metastases at first, so systemic chemotherapy using UFT was performed. Gradually, liver metastases were slightly reduced, and tumor markers (CEA, CA19-9) decreased to the normal range. In April 2001, percutaneous transhepatic tumor biopsy was performed. Histopathological examination revealed a malignant pancreatic endocrine tumor. Long NC had continued by using the UFT regimen. But because tumors had gradually grown since October 2003, the chemotherapy with S-1 was followed by gemcitabine (GEM). The patient has now survived for 7.5 years while receiving the combined chemotherapy of S-1/GEM.

Successful pancreatectomy with en-bloc resection of the celiac artery and portal vein for pancreatic endocrine carcinoma.

Invasion to the celiac axis and portal vein is one reason for the unresectability of pancreatic carcinoma of the body and tail. Some authors advocate a radical distal pancreatectomy with en-bloc resection of the celiac artery and portal vein. However, long-term survival is still rare. We report here on a very rare, long-term survivor of a locally-advanced endocrine carcinoma of the body of the pancreas that was treated by distal pancreatectomy with en-bloc resection of the celiac artery and portal vein. The patient recovered well postoperatively, and has survived for 55 months without evidence of recurrence. The experience gained in the present case suggests that radical pancreatectomy with en-bloc resection of the celiac artery and portal vein is a potential approach that might increase tumor resectability and improve the prognosis of patients with locally-advanced endocrine carcinomas of the pancreas.

Multidetector computed tomography and neuroendocrine pancreaticoduodenal tumors.

PURPOSE: To investigate the accuracy of dedicated pancreatic multidetector computed tomography (MDCT) in the diagnosis of neuroendocrine pancreaticoduodenal tumors (NPTs). MATERIAL AND METHODS: MDCT and other imaging studies in patients with suspected NPTs were identified. Thirty dedicated MDCT studies were done in 23 patients. Fourteen patients (16 operations) subsequently had surgery. Imaging reports were reviewed and findings compared with surgical findings and findings in other imaging studies. RESULTS: Patients with surgery: 19 NPTs (16 extrapancreatic gastrinomas and 3 pancreatic NPTs) were identified at surgery. MDCT identified 16 and somatostatin receptor scintigraphy (SRS) 11 out of 19 tumors. Endoscopic ultrasound detected 11 out of 14 NPTs. Patients without surgery: In 4 out of 9 patients, no NPTs were identified at MDCT. CONCLUSION: Dedicated MDCT of the pancreas can identify many NPTs, including small duodenal and periduodenal tumors, and the detection rate is better than reported in the older literature on CT.

Endoscopic ultrasonography of nonfunctioning pancreatic islet cell tumors with histologic correlation.

BACKGROUND/AIMS: Preoperative differentiation of benign and malignant pancreatic nonfunctioning islet cell tumors remains problematic. The present study aimed to evaluate endoscopic ultrasonography (EUS) features of benign and malignant tumors with histologic correlation. METHODOLOGY: Ten patients with surgically resected nonfunctioning pancreatic islet cell tumors were retrospectively reviewed. RESULTS: EUS demonstrated a homogenous hypoechoic (n=2) or hyperechoic (n=1) mass in the 3 benign tumors. EUS showed a hypoechoic mass with an irregular central hyperechoic portion (n=4), a hyperechoic mass with an irregular central hypoechoic portion (n=1), a cystic mass with a large irregular internal hypoechoic portion (n=1), or a hypoechoic mass within the entire lumen of the main pancreatic duct (MPD) (n=1) in the 7 malignant tumors. Histologically, the irregular central portions of the malignant tumors corresponded to necrosis, hemorrhage, fibrosis with hyalinosis, cystic degeneration, and/or calcification. Complete obstruction of the main pancreatic duct on EUS was observed in the 2 malignant tumors. The echogenicity of the tumors was closely associated with arrangement of tumor cells and quantity of fibrous stroma. CONCLUSIONS: Heterogeneous internal structures and complete obstruction of the main pancreatic duct are considered as important EUS features that are suggestive of malignancy in nonfunctioning pancreatic islet cell tumors.

Intraductal growth of a nonfunctioning endocrine tumor of the pancreas.

Intraductal growth of nonfunctioning endocrine tumors of the pancreas may be very rare, and our survey of literature shows only two cases have been described. We report a case of a 43-year-old man with a nonfunctioning endocrine tumor of the pancreas that uniquely grew within the lumen of the main pancreatic duct (MPD) without ductal involvement and completely obstructed the MPD. Endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) were very helpful to delineate the intraductal growth of the tumor and to determine the resection line of the pancreas. A nonfunctioning pancreatic endocrine tumor is important to consider on differential diagnoses when complete obstruction of the MPD is demonstrated on ERCP. It is speculated that the tumor originated from precursor cells of the pancreatic duct or islet cells adjacent to the MPD and slowly proliferated within the lumen of the MPD.

Octreotide-sensitive ectopic ACTH production by islet cell carcinoma with multiple liver metastases.

We report a 21-year-old woman with ectopic ACTH syndrome due to islet cell carcinoma with multiple liver metastases. On admission, she showed Cushingoid appearance (moon face, central obesity etc.) and had acute respiratory distress syndrome due to pneumocystis carinii pneumonia. Laboratory examination revealed marked elevations of plasma ACTH (735 pg/ml) and cortisol (145 microg/dl) with a profound hypokalemia (2.0 mEq/l). She was found to have multiple masses in the liver and a solid mass in the tail of pancreas by abdominal computerized tomography scanning. Treatment with octreotide successfully reduced elevated plasma ACTH and cortisol levels, and she received frequent transhepatic arterial embolization and chemotherapy. The primary pancreatic tumor was surgically removed, revealing islet cell carcinoma which contained high content of ACTH (100 microg/g wet weight) and abundantly expressed proopiomelanocortin and somatostatin receptor subtype-2 mRNAs as determined by Northern blot analysis. Postoperatively, she was free from symptoms for almost one year. However, progressive enlargement of multiple liver metastases refractory to chemotherapy led her to decide on total hepatectomy and liver transplantation from her father. After liver transplantation, she remained almost free from symptoms for almost one year. However, metastases developed to the mediastinal and paraaortic lymph nodes as detected by 111[In] pentetreotide scintigraphy. Eleven months after liver transplantation, she was again treated with octreotide and, 16 months after, with metyrapone, both of which were effective in reducing ACTH and cortisol levels, respectively, until she died of acute respiratory failure. This case of a young female patient with ectopic ACTH-producing islet cell carcinoma of the pancreas was quite unique in that she survived for 5 years despite the acute onset and rapid progression of the multiple liver metastases at least in part due to the long-lasting favorable response to octreotide and living-related liver transplantation.

Dynamic sonography of pancreatic tumors: comparison with dynamic CT.

OBJECTIVE: The aim of this study was to examine the usefulness of dynamic sonography in the characterization of pancreatic tumors. MATERIALS AND METHODS: IV contrast-enhanced pancreatic sonography (dynamic sonography) with Levovist was performed in 43 patients with pancreatic mass lesions (32 with pancreatic adenocarcinomas, four with inflammatory pancreatic masses, three with islet cell tumors, two with serous cystadenomas, one with a solid and cystic tumor, and one with metastatic pancreatic cancer). We calculated a contrast index using a time-intensity curve: contrast index equals elevation of intensity in the tumor divided by elevation of intensity in the pancreatic parenchyma. We classified the tumors into three groups according to the contrast index: a slightly enhanced group (contrast index < 0.5), a moderately enhanced group (contrast index = 0.5-1.5), and a well-enhanced group (contrast index > 1.5), and we compared these results with those from dynamic CT. RESULTS: The contrast indexes of 32 adenocarcinomas, four inflammatory pancreatic masses, three islet cell tumors, two serous cystadenomas, one solid and cystic tumor, and one metastatic tumor were, respectively, 0.12 +/- 0.095 (mean +/- SD), 0.54 +/- 0.420, 1.74 +/- 0.555, 1.09 +/- 1.380, 1.67, and 2.07. Thirty-five tumors, including all 32 adenocarcinomas, were classified in the slightly enhanced group, three were classified in the moderately enhanced group, and five were classified in the well-enhanced group. In 93% (40/43) of tumors, the grade of enhancement on dynamic sonography was closely correlated with the grade of enhancement on dynamic CT. CONCLUSION: Dynamic sonography can assist in the characterization of pancreatic tumors.

Differential diagnosis of benign versus malignant nonfunctioning islet cell tumors of the pancreas: the roles of EUS and ERCP.

BACKGROUND: Differentiation between benign and malignant nonfunctioning islet cell tumors of the pancreas before surgery is often difficult. The roles of EUS and ERCP were evaluated in the differential diagnosis of these tumors. METHODS: Seven patients with histologically confirmed nonfunctioning islet cell tumors (4 benign, 3 malignant) underwent EUS and ERCP. OBSERVATIONS: EUS demonstrated a homogeneous hypoechoic mass or a hypoechoic mass with a regular central echogenic area in the 4 cases of benign tumor, and a hypoechoic mass with an irregular central echogenic area in all 3 cases of malignant tumor. The irregular central echogenic area corresponded to severe hemorrhage, necrosis, or fibrosis with hyalinosis (hyaline degeneration) on pathologic examination. ERCP demonstrated displacement or complete obstruction (because of ductal invasion) of the main pancreatic duct in 2 patients with malignant tumors and no abnormalities in the other 5 cases. CONCLUSIONS: In patients with nonfunctioning islet cell tumors, a hypoechoic mass with an irregular central echogenic area on EUS or complete obstruction of the main pancreatic duct on ERCP suggests malignancy.

Nonfunctioning islet cell carcinoma of the pancreas associated with massive intra-abdominal hemorrhage.

Pancreatic islet cell tumors are rarely associated with intra-abdominal hemorrhage. We report herein a rare case of nonfunctioning islet cell carcinoma associated with massive hemorrhage into the abdominal cavity caused by spontaneous rupture of the tumor. A 44-year-old man presenting with sudden upper abdominal pain was admitted to his local hospital on April 18, 1994. On April 19, a laparotomy was performed with the diagnosis of peritonitis. Massive hemorrhage of unknown origin occurred, and he was transferred to our hospital in a state of hypovolemic shock. Imaging findings revealed massive hematoma in the abdominal cavity and a hypervascular tumor arising from the body of the pancreas. Because the hemorrhage was life-threatening, an emergent re-laparotomy was performed on April 20. Apart from the massive hemorrhage, a pancreatic tumor (60 x 35 x 30 mm in size) with spontaneous rupture was noted. Distal pancreatectomy, combined with splenectomy and removal of the hematoma, was performed. Histological findings revealed an islet cell carcinoma of the pancreas with venous invasion. Peritoneal dissemination, liver metastasis, and lymph node metastasis were not observed. The patient is alive without recurrence 6 years and 5 months after the operation.

Microcytic adenoma coexistent with low-grade malignant islet cell tumor of the pancreas.

We report a case of microcystic (glycogen-rich) adenoma of the whole pancreas with coexistent pancreatic low-grade malignant islet cell tumor in a 29-year-old woman. She complained of nausea, vomiting, and growing abdominal mass. Abdominal computed tomography showed multiple cysts in the whole pancreas and a calcified solid mass in the pancreatic head. A Whipple's operation and total pancreatectomy with splenectomy was performed to treat pancreatic cystic neoplasm. The pancreas was entirely replaced by variable-sized, multilocular cysts, which were lined by a flattened-to-cuboidal glycogen-rich epithelium. Furthermore, in the head of the pancreas, a focal yellowish solid mass showed a positive reaction for chromogranin A and neuron-specific enolase. Careful examination of the pancreas is warranted in cases of microcystic adenoma to rule out a possible coexistent pancreatic malignancy.