Neuroendrocine pancreatic tumours: clinical presentation,biochemical and histopathological findings in 84 patients

Abstract. A prospective study has been performed on 84 patients with endocrine pancreatic tumours evaluated at the Medical Department in Uppsala. Available information concerning the patients' presenting symptoms, age at diagnosis, clinical syndrome, tumour location, location of metastases, diagnostic radiology, biochemical and histopathological findings has been analysed. Our results indicate that most patients initially show rather vague and non-specific symptoms, with dyspepsia and pain being the most frequent presenting features. The median delay between appearance of the first symptom and diagnosis was 2 years; the delay was 3 5 months in sporadic cases and 14.5 months in familial cases. In spite of improvements in diagnostic methods, the median age at diagnosis (53 years) has not been reduced, and most patients are encountered when the tumour has reached an advanced stage. There is a need for a method of screening patients with still uncharacteristic abdominalsymptoms for a neuroendocrine tumour. The presence of elevated levels of plasma chromogranin in all patients with a proven tumour suggests that such possibilities exist, and the use of this biochemical marker in the future might reduce the age at diagnosis and thus improve the likelihood of cure and survival of patients with endocrine pancreatic tumours.     

Difficult diagnosis of a pancreatic paraganglioma

INTRODUCTION: The paraganglioma is a rare tumour that can sometimes develop near to the pancreatic gland and can occasionally mimic an intra pancreatic mass. Invasive investigations with puncture or primary surgical resection must be avoided because of the risk of vital complications. EXEGESIS: We report on the case of a 41 years old woman presenting with a mass apparently affecting the pancreatic gland. She also presented with malaises. Paraganglioma was suspected because of the malaises and the blood pressure crises. The diagnosis was permitted by the findings of high urinary metanephrine levels. So the tumour was resected without previous fine needle aspiration and with specific anaesthetic measures. No complication was observed. CONCLUSION: When a patient presents with a pancreatic mass, physician must carefully take into account the possibility of a paraganglioma particularly when malaises are present.     

Parathyroid hormone-related peptide in pancreatic neuroendocrine tumours associated with hypercalcaemia

BackgroundHypercalcaemia is a common paraneoplastic syndrome. In the context of pancreatic neuroendocrine tumours, it is occasionally caused by secretion of parathyroid hormone-related peptide (PTH-rP).Case outlinesTwo patients are reported in whom persistent hypercalcaemia was traced to a large neuroendocrine pancreatic tumour hypersecreting PTH-rP. Resection of the tumour reduced serum levels of calcium and PTH-rP transiently in each case until the patient developed bulky metastatic disease. A 33-year-old woman remained hypercalcaemic after the removal of all four hyperplastic parathyroid glands had rendered circulating parathormone levels undetectable. Radical distal pancreatectomy was followed over the next 4 years by operative debulking of liver metastases, multiple hepatic artery embolisations.octreotide injections and repeated admissions for intravenous fluid and biphosphonate therapy. A 41-year-old man presented with hypercalcaemia as well as features of somatostatinoma syndrome. Symptomatic improvement after radical distal pancreatectomy was short-lived, and hepatic artery embolisation failed to control his rapidly progressive disease.DiscussionMalignant hypercalcaemia associated with a neuroendocrine pancreatic tumour hypersecreting PTH-rP is difficult to treat and can be life-threatening. Aggressive surgical treatment is recommended initially, while somatostatin analogues and hepatic artery embolisation are alternative therapeutic options for metastatic disease.     

Value of endoscopic ultrasound guided fine needle aspiration biopsy in the diagnosis of solid pancreatic masses

AIM: To assess the feasibility and diagnostic accuracy of endoscopic ultrasound guided fine needle biopsy (EUS-FNAB) in patients with solid pancreatic masses. METHODS: Ninety nine consecutive patients with pancreatic masses were studied. Histological findings obtained by EUS-FNAB were compared with the final diagnosis assessed by surgery, biopsy of other tumour site or at postmortem examination, or by using a combination of clinical course, imaging features, and tumour markers. RESULTS: EUS-FNAB was feasible in 90 patients (adenocarcinomas, n = 59; neuroendocrine tumours, n = 15; various neoplasms, n = 6; pancreatitis, n = 10), and analysable material was obtained in 73. Tumour size (>/= or < 25 mm in diameter) did not influence the ability to obtain informative biopsy samples. Diagnostic accuracy was 74.4% (adenocarcinomas, 81.4%; neuroendocrine tumours, 46.7%; other lesions, 75%; p<0.02). Overall, the diagnostic yield in all 99 patients was 68%. Successful biopsies were performed in six patients with portal hypertension. Minor complications (moderate bleeding or pain) occurred in 5% of cases. CONCLUSIONS: EUS-FNAB is a useful and safe method for the investigation of pancreatic masses, with a high feasibility rate even when lesions are small. Overall diagnostic accuracy of EUS-FNAB seems to depend on the tumour type.     

Digestive neuroendocrine tumours: diagnosis and treatment in Italy. A survey by the Oncology study Section of the Italian Society of Gastroenterology (SIGE)

BACKGROUND: New insights in the diagnosis and treatment of digestive neuroendocrine tumours have prompted a renewed interest in these rare and complex diseases. AIM: To establish how many new cases of digestive neuroendocrine tumours were diagnosed, and how they were treated, at gastroenterological centres across Italy during a two-year period (1997-1998). METHODS: The 12 centres taking part filled in a data collection form reporting type of tumour, methods of diagnosis and therapeutic strategies adopted in each case. Data were collected and analysed by the authors of the present report. RESULTS: Data refer to 98 patients, 22 with functioning and 76 with non-functioning digestive neuroendocrine tumours [50 carcinoids, 48 pancreatic endocrine tumour syndromes]. Primary tumours were localised in 96% (38% with metastases) of non-functioning and 81% (50% with metastases) of functioning tumours. These were surgically removed in >80% of patients in both groups. Somatostatin analogue treatment, with or without interferon, was administered in 35% of patients, while chemotherapy was used in 9% and 23% of functioning and non-functioning tumours, respectively. The imaging study always included a computed tomography scan (20% helical computed tomography). Magnetic resonance and somatostatin receptor scintigraphy were also performed, the former in 41% and 21% of the two (functioning and non-functioning tumour) groups, the latter in 45% and 30%. CONCLUSIONS: The number of functioning digestive neuroendocrine tumours reported was lower than expected. Surgery plays a major role in the treatment of these tumours in all centres. Overall, in only a small number of patients was a multidisciplinary approach applied.     

Endoscopic ultrasound-guided ethanol ablation of pancreatic neuroendocrine tumours: A case study and literature review

Here we offer a review of the literature regarding endoscopic ultrasound-guided ethanol ablation for pancreatic neuroendocrine tumours and describe the case of a cystic tumour completely ablated after a multisession procedure. A total of 35 PubM ed indexed cases of treated functioning and non-functioning pancreatic neuroendocrine tumours resulted from our search, 29 of which are well-documented and summarised. Endoscopic ultrasound-guided ethanol ablation appears as a local, minimally invasive treatment of pancreatic neuroendocrine tumours, suitable for selected patients. This technique appears feasible, relatively safe and efficient, especially when applied to symptom relief in functioning tumours, aiming at loss of endocrine secretion. For non-functioning tumours, where the goal is complete tissue ablation, eus guided ethanol ablation can provide good results for patients who are unfit for surgery or for those who refuse surgical resection. Its role in "fit for surgery" patients requires assessment through further studies.     

Rectal neuroendocrine tumours and the role of emerging endoscopic techniques

Rectal neuroendocrine tumours represent a rare colorectal tumour with a 10 fold increased prevalence due to incidental detection in the era of colorectal screening. Patient outcomes with early diagnosis are excellent. However endoscopic recognition of this lesion is variable and misdiagnosis can result in suboptimal endoscopic resection with subsequent uncertainty in relation to optimal long-term management. Endoscopic techniques have shown particular utility in managing this under-recognized neuroendocrine tumour.     

Gangliocytic paraganglioma--a rare differential diagnosis of a submucosal duodenal tumor

We report on the case of a 36-year-old male patient who was found to have a submucosal duodenal tumour during the diagnostic work-up of gastrointestinal bleeding. After exclusion of other tumour manifestations complete endoscopic resection was performed. Histologically a gangliocytic paraganglioma was diagnosed, a very rare type of a duodenal neuroendocrine tumour. This case report discusses the epidemiology, diagnostic work-up and therapeutic options for this rare tumour type.     

Neuroendocrine tumors of the gastroenteric canal. Anatomopathological and diagnostic-therapeutic definition. Description of a case with a rare cecal localisation

The authors take the case of a neuroendocrine tumour of the cecum as the starting point for an analysis of the anatomopathological and diagnostic-therapeutic aspects of these neoplasms. Furthermore, the authors underline that neuroendocrine tumours (NET) of the colon represent an extremely rare nosological entity and that they are heterogeneous from a clinical and biochemical point of view, thus making a reliable preoperative diagnosis a problem that is still difficult to resolve today.     

A Preoperative Prognostic Score for Resected Pancreatic and Periampullary Neuroendocrine Tumours

Background/Aims: To identify potential preoperative prognostic factors in resected pancreatic and periampullary neuroendocrine tumours. Methods: Clinico-pathological data for 54 consecutive patients with pancreatic or periampullary neuroendocrine tumours referred to our institution over a 10-year period were identified from a prospective database. Results: 34 patients underwent pancreatic resection (12 males, 22 females; median age 54 (IQR 44–71) years). There was a single 30-day mortality (3%). Nodal status (log rank, p = 0.652), microscopic resection margin involvement (p = 0.549) and tumour size (p = 0.122) failed to exhibit any prognostic value. Only the presence of malignant tumour characteristics was associated with poorer overall survival (p = 0.008). Analysis of preoperative parameters showed that age >60 years (p = 0.056), platelet-lymphocyte ratio 1300 (p = 0.008), alkaline phosphatase levels 1125 U/l (p = 0.042) and alanine aminotransferase >35 U/l (p = 0.016) were adverse prognostic factors. A risk stratification score was generated where each adverse preoperative parameter was allocated a score of 1. A cumulative score of ≤1 was defined as low risk, while a score of ≥2 was defined as high risk. Median overall survival in the high-risk group was 10.4 months, while the median survival in the low-risk group was 160 months (p > 0.001). Conclusion: Significant prognostic information can be gained from routine preoperative biochemistry and haematology results in resected pancreatic and periampullary neuroendocrine tumours. These findings merit further evaluation in a larger patient cohort.     

The importance of the measurement of circulating markers in patients with neuroendocrine tumours of the pancreas and gut

The measurement of general and specific biochemical markers in patients with neuroendocrine tumours assists with diagnosis and gives an indication of the effectiveness of treatment and they may be used as prognostic indicators. There is much agreement that chromogranin A is the most universally helpful marker; it is found to be elevated in the circulation of about 90% of patients with metastatic neuroendocrine tumours and there are several excellent commercially available kits which give reliable estimations. Specific markers are useful for diagnosis also, and are helpful indicators of the effectiveness of treatment, particularly where tumour bulk may not change as much as tumour activity. Sporadic pancreatic neuroendocrine tumours may secrete more than one peptide and this indicates a worsening prognosis. Because of the wide variation in the progression of neuroendocrine tumours, a prognostic indicator gives a significant advantage to the clinician in order to facilitate optimum treatment at the optimum stage of disease. Both chromogranin A and neurokinin A have been used as powerful prognostic indicators for midgut carcinoid tumours.     

EUS-guided FNA in the diagnosis of pancreatic neuroendocrine tumors before surgery

BACKGROUND: The use of EUS for precise preoperative evaluation of pancreatic neuroendocrine tumors is well established; up to 80% of insulinomas can be localized. However, the EUS appearance of pancreatic neuroendocrine tumors can be similar to that of benign peripancreatic lymph nodes. The aim of this study was to evaluate the role of EUS-guided FNA in this setting. METHODS: Thirty patients (18 women, 12 men) with 33 pancreatic/peripancreatic lesions confirmed by surgery underwent EUS-guided FNA between February 1997 and September 2002. Transabdominal US and CT were obtained in all patients before EUS. The diagnosis of pancreatic neuroendocrine tumor was established based on morphologic appearance and immunohistochemical staining of cytologic and surgical specimens. RESULTS: EUS detected 32 of the 33 (96.9%) lesions (mean diameter 20 mm, range 5-97 mm). There was one complication (abdominal pain). For the 30 patients, the following diagnoses were made: functioning pancreatic neuroendocrine tumor (16 patients), non-functioning pancreatic neuroendocrine tumor (7), peripancreatic lymph node (5), inflammatory intrapancreatic nodule (1), and peripancreatic splenosis (1). Sensitivity, specificity, positive and negative predictive values, and accuracy of EUS-guided FNA were 82.6%, 85.7%, 95%, 60%, and 83.3%, respectively. There was one false-positive diagnosis by EUS-guided FNA and 4 false-negative diagnoses. In two of the latter cases, EUS-guided FNA was unsuccessful. CONCLUSIONS: EUS-guided FNA is accurate and safe for the diagnosis of pancreatic neuroendocrine tumor and may have a role in determining management strategy.     

Pancreatic Hamartoma Difficult to Diagnose Preoperatively

Abdominal ultrasonography in a 70-year-old woman showed a hypoechoic mass, 14 mm in diameter, in the pancreatic body. Computed tomography showed a mass with contrast effect in the pancreatic body. Test results for endocrine factors or tumor markers were normal. The initial consideration was nonfunctional pancreatic neuroendocrine tumor. Over 8 years of monitoring, the tumor diameter increased to 18 mm, until pancreatic tumor enucleation was performed. The postoperative diagnosis was pancreatic hamartoma, a rare type of benign pancreatic tumor. The preoperative diagnosis of pancreatic hamartoma is difficult, but consideration must be given to the possibility of hamartoma when encountering pancreatic tumors.     

Operative tumour yield obviates preoperative pancreatic tumour localization in multiple endocrine neoplasia type 1

Abstract. The efficiency of pancreatic tumour localization was prospectively evaluated in 12 consecutive patients with multiple endocrine neoplasia type 1 (MEN1), who were subjected to extirpation of 56 islet cell neoplasms of 0.2–4 cm in diameter (mean 0.8 cm) during pancreatic resection and enucleation. Computed tomography, angiography of the coeliac trunc and superior mesenteric artery, and percutaneous ultrasound correctly localized 7–12% of the tumours and 21–37% of the 19 lesions measuring at least one centimetre in diameter. Transhepatic portal vein sampling correctly located tumour sites in the proximal or distal portions of the pancreas in four out of six patients, but demonstrated unsatisfactory specificity. Intra-operative ultrasound and bidigital palpation of the pancreas had overall sensitivities of 86 and 45%, respectively, and eight lesions below 0.3 cm in diameter remained undetected with intraoperative ultrasound. It is concluded that diagnosis of endocrine pancreatic neoplasms is biochemical in MEN1 and that broad screening of tumour markers efficiently reveals pancreatic involvement decades before the development of a clinically overt disease. Intra-operative ultrasound is a requisite for pancreatic endocrine surgery in MEN1, and it obviates the need for conventional pancreatic imaging unless a pre-operative search for metastatic disease and anatomical aberrations is considered important.     

Pancreatic schwannoma,an extremely rare and challenging entity: Report of two cases and review of literature

Pancreatic schwannoma is a rare benign tumor, for which the preoperative and intraoperative definitive diagnosis is quite challenging. We present the clinical, radiological and pathologic features of two primary pancreatic schwannomas identified in our pathology database over a period of 30 years at our tertiary care hospital. To better understand the clinico-pathological and radiological features of this entity, we provide a comprehensive review of 73 cases described in the English literature, along with our two cases. This review will especially focus on preoperative and intraoperative diagnosis to assess their accuracy for pancreatic schwannoma. The three most common preoperative diagnoses based on imaging for pancreatic schwannomas were cystic neoplasm (56%), pancreatic neuroendocrine tumor (29%) and mucinous cystic neoplasm (26%). Imaging could not definitely diagnose pancreatic schwannoma in any of the reported cases. To obtain a definite diagnosis before surgery, 25 cases underwent imaging-guided fine-needle aspiration (FNA)/biopsy, of which 60% were correctly reported as benign with definite diagnosis of pancreatic schwannoma in 48%. A higher diagnostic accuracy was observed in biopsies (71%) than FNA (37%). In addition, an intraoperative frozen section was carried out in 15 cases, and 47% were correctly diagnosed. Despite relatively low accuracy, preoperative histological assessment can be helpful in surgical managment. A core tissue specimen is recommended to improve the diagnostic accuracy in this setting.     

The ultimate biochemical diagnosis of endocrine pancreatic tumours in MEN-1

Öberg K, Skogseid B (University Hospital, Uppsala, Sweden). The ultimate biochemical diagnosis of endocrine pancreatic tumours in MEN-1 (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 471–6. Multiple endocrine neoplasia type 1 (MEN-1) is a well characterized hereditary syndrome with the occurrence of primary hyperparathyroidism (HPT) in combination with pancreatic-duodenal endocrine and anterior pituitary tumours. The diagnosis of MEN-1, the possible probands, necessitates the recognition of at least two or three lesions classically associated with the syndrome whilst only one of them is required for individuals belonging to established MEN-1 kindreds. A distinct feature of MEN-1 comprises the multiplicity of organ involvement, the multicentricity of tumours within the affected organs as well as the complex pattern of the clinical signs of these tumours and their sometimes temporarily variable profile of hormone excess. Thorough screening studies have demonstrated that the MEN-1 trait is biochemically detectable virtually two decades prior to clinically overt disease. The primary biochemical screening programme for MEN-1 includes serum prolactin and insulin growth factor 1 (IGF-1) for pituitary lesions, intact PTH and albumin corrected total serum calcium for the parathyroids and for duodenal/pancreatic tumours serum glucose, insulin, proinsulin, pancreatic polypeptide, glucagon, gastrin and plasma chromogranin A. Furthermore a standardized meal stimulatory test analysing serum polypeptides (PP) and gastrin is recommended. Our current primary screening procedure has yielded about 10% false positives when compared with RFLP data. Pancreatic endocrine tumour diagnosis must be biochemically established since radiology fails to show lesions in half of the patients. Pancreatic involvement in young MEN-1 patients is most consistently demonstrated by analysing serum insulin, proinsulin, PP as well as plasma glucagon chromogranin A levels, which have exhibited sensitivities of 56, 67, 37 and 60%, respectively. Serum PP is a non-specific marker of islet cell tumours that should be applied in conjunction with other peptide markers. Elevation of basal serum gastrin generally indicates the presence of advanced pancreatic tumour involvement or duodenal carcinoids. Early diagnosis of pancreatic endocrine tumours in MEN-1 is enhanced by the use of a standardized meal stimulation test with measurements of serum PP and gastrin response. This test was the most sensitive test and substantiated the presence of tumour in 75% of individuals whose mean age was 25 years. False-positive stimulation due to the meal test has been found in about 10% of previous investigated individuals. The diagnosis of MEN-1 pancreatic tumours is based on biochemical screening alone and it has been substantiated that an unequivocal rise in pancreatic tumour markers precedes radiological detection of these lesions by at least five years.     

Co-existence of a huge pseudocyst and mucinous cystadenoma: report of a case and the value of magnetic resonance imaging for differential diagnosis

Co-existence of a pancreatic pseudocyst and a neoplastic cyst is rare and their differential diagnosis is difficult if the patient has an atypical history as well as subclinical symptoms. The formation of a pseudocyst under such circumstances is usually the result of downstream ductal obstruction by the neoplasm. Two large cysts were found in a 43-year-old woman who had symptoms of gastric outlet obstruction that were the result of external compression by one of the cysts. Magnetic resonance imaging was superior to computed tomography, discriminating between the internal contents and surrounding tissue of the two cysts, enabling the correct preoperative diagnosis of a pseudocyst co-existing with a mucinous cystadenoma to be made. It was most unusual for the pseudocyst to be located downstream of the mucinous tumour, ruling out ductal obstruction by the tumour in its pathogenesis. A possible explanation for the pseudocyst formation in this case was pancreatic juice accumulation in the space of the lesser sac after pancreatic parenchymal destruction by the mucinous tumour.     

A rare intracardiac mass: cardiac paraganglioma

It is very rare for heart tissue to give rise to a primary paraganglioma. Here, we report the observation of such a tumour in a 34-year-old woman who presented with symptoms of pulmonary venous congestion. The findings from echocardiography were consistent with the diagnosis of a myxoma that was partially occluding the left atrium. Surgery was performed in which a large (6 cm x 5 cm x 3 cm), non-lobulated solid tumour was resected from the posterior wall of the atrium. Upon histologic evaluation, this was determined to be a cardiac paraganglioma.     

Imaging of neuroendocrine tumours (CT/MR/US)

Neuroendocrine tumours may be broadly divided into pancreatic endocrine tumours (PETs) and carcinoid neuroendocrine tumours (NETs). In both cases, patients may present with a clinical syndrome related to hormone secretion by the tumour. In these cases, cross-sectional imaging plays an important role in the localization of the primary tumour, the detection of metastases, and the assessment of response to treatment. Computed tomography (CT) is established as the primary modality, although following technological advances detection rates on magnetic resonance imaging (MRI) are now challenging those of CT. Endoscopic ultrasound has an important role in the preoperative assessment of the pancreas where a small functioning tumour or the possibility of multiple tumours is suspected. The sensitivity for the detection of small functioning tumours depends upon optimal technique, whichever modality is used. Non-functioning tumours frequently present late with mass effect, as there is no accompanying clinical syndrome. Carcinoid neuroendocrine tumours are most frequently localized on CT. MRI is usually used as a problem-solving tool. As technology evolves, detection rates may continue to improve, and the highest sensitivities may be achieved by a combination of different modalities.