Benign and malignant tumours of the pancreatic islets are

common enough to be encountered occasionally during a

lifetime in a busy medical practice.

These tumours secrete large amounts of potent hormones that

lead to profound physiologic disturbances that are responsible

for distinctive clinical syndromes.

Before considering islet cell tumours a brief discussion of the

development and function of normal islets will serve to set

this group of intriguing tumours in perspective.

Neuroendocrine tumours of pancreas are not common

(prevalence rate of less than 1 per 1000,000 population) but,

because of the good prognosis and often early presentation,

relative to pancreatic adenocarcinoma, they are

disproportionately represented in tumour resection

specimens of pancreas (14% of cases).

In most published series approximately 70-80% of neuroendocrine

tumors are categorized as functional- i.e., they secrete

a recognized hormone causing a distinct hormonal

syndrome.

Insulinomas are the most common functional pancreatic

endocrine tumors.

In decreasing order of frequency the other encountered functional

tumours include gastrinoma, vipoma, glucagonoma, and

somatostatinoma.

Functional tumours tend to present at an earlier age than

non-functional ones.

The latter usually present with symptoms such as obstruction, or as

abdominal masses or as incidental  findings on CT examinations,

etc.

Diagnosis

Neuroendocrine tumours can usually be readily diagnosed on

hematoxylin and eosin staining.

A variety of histological patterns can be seen

(trabecular, solid, acinar) but these patterns bear no

relationship to the hormonal status of the tumour or

 its malignant potential.

Immunocytochemistry can be used to show neuroendocrine

differentiation (Chromogranin A , PGP 9.5 , synaptophysin)

as well as the presence of pancreatic hormones (insulin,

glucagons, somatostatin and pancreatic polypeptide)

and gastrin.

Many tumours on the analysis will be shows to be multi-hormonal,

although cells producing the hormone causing the syndrome

are liable to predominate.

 Some tumors will be shows to contain hormones such

as pancreatic polypeptide or somatostatin in the absence

of any obvious hormonal clinical syndrome.

By convention, these tumours are classified as

non-functional.

The main differential diagnosis of a non-functional pancreatic

neuroendocrine tumour is solid and cystic tumour of the pancreas

which tends to present in young women as a large, symptomatic

abdominal mass arising in the pancreas.

When resected this lesion often shows areas of necrosis

(a rare finding even in malignant pancreatic

neuroendocrine tumours) and a careful search will usually

show areas of the tumour in which a definite papillary

pattern can be demonstrated.

This, coupled with negative immunocytochemical findings for

neuroendocrine markers, should allow the correct diagnosis to be

made.

It is not unusual to find difficulty in demonstrating the

relevant hormone immunocytochemically in a

functional pancreatic neuroendocrine tumour.

The cells in many tumours are relatively "incontinent", such that

while they may secrete large quantities of hormone they may store

relatively little.

Immunocytochemistry detects stored prohormone within cells of

relatively little staining of the relevant hormone may be seen.

In situ hybridization for hormonal messenger RNA is a possible way

round this problem since it reflects the rate of hormonal synthesis

rather than quantity of hormone stored

within a cell.

A preliminary study of insulinoma has confirmed that in

situ hybridization may indeed be more sensitive than

immunocytochemistry in defining functional tumours.

Benign or malignant?

The standard statement on this subject is that the only two definite

criteria of malignancy in pancreatic endocrine neoplasms

are invasion of adjacent organs and the

presence of metastases.

However, these features are only present to 30-50% of

resected tumours which subsequently prove to be

malignant.

Have recent studies advanced our ability to predict the behavior of

tumours which, at the time of surgery appear to be confined to the

pancreas?

Since over 90% of insulinomas are benign this question is

not often raised when these tumors are encountered.

Among the remainder, the presence of an intrapancreatic invasive

growth pattern, the demonstration of nuclear pleomorphism,

aneuploidy or cytoplasmic alfa-HCG all fail to act as prognostic

predictors.

Progesterone receptor is present more commonly in benign

tumours but the difference is insufficiently clear cut to be

of diagnostic use.

Two Italian studies have shown that measures of tumour

proliferation give the best predictive value of subsequent

behavior.

In Pelosi’s study, the actual survival of all patients with a

Ki-67 proliferative index greater than 5% was zero within 7 years,

where as in those with a lower index more than

80% survival longer than 10 years.

Similar findings were demonstrated in the non-functioning

pancreatic endocrine tumours studied by La Rossa, although

here the cut-off Ki-67 proliferative index was 2%.

Other criteria found to be statistical significant prognostic value in

the latter study were the presence of tumour thrombi within

capsular blood vessels, perineural space infiltration and a

tumour size greater than 4 cms.

As Ki-67 can now be immunostained on routinely fixed tissues these

observations should be applicable to clinical use.

Endocrine tumors of the pancreas represent 1% to 2% of all pancreatic neoplasms. The tumors tend to have an indolent behavior, and long-term survival is common. There is no gender or age predilection. Patients can present with symptoms due to hormonal excess or a local mass effect or be asymptomatic. The tumors tend to be solid and well circumscribed. Typical microscopic findings include an organoid pattern of growth, with cells containing scant to moderate amounts of cytoplasm, and nuclei with dispersed chromatin and inconspicuous nucleoli. The morphologic spectrum of these tumors can be variable, and the differential diagnosis includes chronic pancreatitis with neuroendocrine hyperplasia, ductal adenocarcinoma, solid pseudopapillary tumor, acinar cell carcinoma, and pancreatoblastoma. The classification of these tumors remains controversial, and prognosis is difficult to predict, but important features include metastasis and invasion of adjacent structures. Resection remains the mainstay of surgical treatment. It is important to be aware that unusual morphologic variants of pancreatic endocrine tumors are common, and immunohistochemical stains can help avoid misdiagnosis

Pancreatic endocrine tumors.Chirurgia (Bucur). 2006;101(2):175-81.

Incidence of the endocrine tumors of the pancreas is about 4 to 10/1.000.000 peoples. We present 10 cases of endocrine pancreatic tumors which were operated in the First Surgical Clinic Iaşi in the last 20 years (1984-2003); these cases represent about 2.21% from all the pancreatic tumors (454 cases). It was 4 insulinoma, 2 gastrinoma, 2 gastrinoma associated with other endocrine neoplasia (Wermer syndrome) and 2 non-functioning endocrine pancreatic tumors. Female/men ratio was 9/1 and median age was about 41.9 yo (27-67 yo). In the four cases of insulinoma (all females) the diagnosis was delayed by two to five years due to misinterpretation of neurological symptoms generated by hypoglycemia. The diagnosis of insulinoma was based on Whipple triad, high plasma insulin levels associated with low plasma glucose levels, as well as the symptomatic relief after intravenous glucose injection. The surgical option was based on biological data, ultrasonography, computed tomography and arteriography. In two cases the localization of the insulinoma was established only by intraoperative ultrasonography. All tumors were localized in the tail of pancreas. In three cases we decided for a distal pancreatic resection with splenectomy and in one case for spleen preserving left pancreatectomy. Postoperative course was uneventful and all the symptoms disappeared. The diagnosis was confirmed on pathological examination in all cases. We also present two cases of gastrinoma with multiple ulcers and multiple surgical interventions for haemorrhage and perforation with peritonitis. Both patients died and diagnosis of pancreatic endocrine tumors was post-mortem. The two patients with Wermer syndrome also had ulcers complicated with haemorrhage and peritonitis and parathyroid adenoma. One case also had ante-hypophyseal and pituitary adenoma and the other had thyroid colloid hypertrophy. We performed left pancreatectomy with spleen preservation in one case and enucleation associated with total gastrectomy in the second case. The two cases of non-functioning pancreatic endocrine tumors had a non-specific symptoms. Diagnostic was established by abdominal ultrasound exam. We performed spleno-pancreatectomy in one case and pancreatectomy with spleen preservation in the other patient. Postoperative course was un-eventful.

Endocrine tumors of the pancreas: experience in the ABC Medical Center.Rev Gastroenterol Mex. 2006 Jul-Sep;71(3):296-301.

OBJECTIVES: To analyze presentation, diagnosis and treatment of islet cell tumors at the ABC Medical Center. MATERIALS AND METHODS: Medical records of the 7 patients with endocrine tumors diagnosed between 1995 and 2005 were reviewed and analyzed, with emphasis to clinical, biochemical and radiological characteristics, surgical treatment and outcome. RESULTS: There were 3 insulinomas, 1 gastrinoma, 1 VIPoma, and 2 non-functioning tumors. All insulinomas presented the Whipple's triad. The tumor was localized before surgery in 2 cases. In all patients intraoperative ultrasound confirmed the tumor and enucleation was performed in all three. The patient with gastrinoma was diagnosed by endoscopy in the presence of metastatic disease, therefore no surgical treatment was performed. The patient with VIPoma, presented the typical secretory diarrhea. A tumor in the pancreatic head was found and it was resected by pancreaticoduodenectomy. Histology revealed a malignant lesion. Both non functioning tumors were found by imaging studies, one benign tumor was treated by central pancreatectomy and the other was malignant and underwent distal en-block pancreatectomy. Immunohistochemistry was positive for VIP in the benign lesion. Two of the 3 malignant tumors have died and one is alive with recurrent disease. CONCLUSIONS: Distribution of islet cell tumors in our series followed the usual patterns. In all functioning lesions hormonal production was identified before surgery. Imaging studies localized the tumor in 7 of the 8 patients. Surgical resection cured all benign tumors.

Surgical treatment of gastric, enteric, and pancreatic endocrine tumors Part 1. Treatment of primary endocrine tumors.J Chir (Paris). 2005 May-Jun;142(3):132-49.

Endocrine tumors (ET) of the digestive tract (formerly called neuroendocrine tumors) are rare. They are classified into two principal types: gastrointestinal ET's (formerly called carcinoid tumors) which are the most common, and pancreaticoduodenal ET's. Functioning ET's secrete polypeptide hormones which cause characteristic hormonal syndromes. The management of ET is multidisciplinary. Poorly-differentiated ET's have a poor prognosis and are treated by chemotherapy. Surgical excision is the only curative treatment of well-differentiated ET's. The surgical goals are to: 1. prolong survival by resecting the primary tumor and any nodal or hepatic metastases, 2. control the symptoms related to hormonal secretion, 3. prevent or treat local complications. The most common sites of gastrointestinal ET's ( carcinoids) are the appendix and the rectum; these are often small (<1 cm), benign, and discovered fortuitously at the time of appendectomy or colonoscopic removal. Ileal ET's, even if small, are malignant, frequently multiple, and complicated in 30-50% of cases by bowel obstruction, mesenteric invasion, or bleeding. The carcinoid syndrome (consisting of abdominal pain, flushing, diarrhea, hypertension, bronchospasm, and right sided cardiac vegetations) is caused by the hypersecretion of serotonin into the systemic circulation; it occurs in 10% of cases and is usually associated with hepatic metastases. More than half of the cases of pancreatic ET are non-functional. They are usually malignant and of advanced stage at diagnosis presenting as a palpable or obstructing mass or as liver metastases. Insulinoma and gastrinoma (cause of the Zollinger-Ellison syndrome) are the most common functional ET's. 80% are sporadic; in these cases, tumor size, location, and malignant potential determine the type of resection which may vary from a simple enucleation to a formal pancreatectomy. In 10-20% of cases, pancreaticoduodenal ET presents in the setting of multiple endocrine neoplasia (NEM type I), an autosomal-dominant genetic disease with multifocal endocrine involvement of the pituitary, parathyroid, pancreas, and adrenal glands. For insulinoma with NEM-I, enucleation of lesions in the pancreatic head plus a caudal pancreatectomy is the most appropriate procedure. For gastrinoma with NEM-I, the benefit of surgical resection for tumors less than 2-3 cm in size is not clear. The lesions are frequently small, multiple, and widespread and recurrence is frequent after excision. The long-term prognosis is nevertheless fairly good. But the eventual development of liver metastases which are the most common cause of mortality still argues for an aggressive surgical approach in the early stages of the disease.

Neuroendocrine carcinomas of the pancreas with ‘rhabdoid’ features. Am J Surg Pathol 2003;27:642–649.

Neuroendocrine carcinomas of the pancreas are rare neoplasms whose morphologic features generally mirror those seen in neuroendocrine tumors in other organs. Rarely, however, they may display unusual morphologic appearances that can introduce difficulties for diagnosis. We report four cases of primary neuroendocrine carcinomas of the pancreas (islet cell tumors) that were characterized by prominent "rhabdoid" features of the tumor cells. The lesions occurred in two men and two women 37-79 years of age who presented with symptoms of biliary obstruction and epigastric pain; one patient had recurrent gastric ulcers and an elevated gastrin level. The tumors were located in the head and tail of the pancreas and measured 2.5-4.5 cm in greatest diameter. Histologic examination revealed sheets of monotonous tumor cells with uniform round nuclei showing dispersed chromatin and containing abundant densely eosinophilic cytoplasmic inclusions that displaced the nuclei toward the periphery. In all cases, the rhabdoid elements appeared to merge with areas showing a more conventional neuroendocrine morphology. Immunohistochemical studies in all cases showed strong cytoplasmic positivity of the rhabdoid tumor cells for chromogranin, synaptophysin, and cytokeratin. Recognition of this unusual morphologic appearance is of importance to avoid mistaking these lesions for other types of malignant neoplasm.

Telomerase activity in pancreatic endocrine tumors.Am J Gastroenterol. 2002 Apr;97(4):1022-30.

OBJECTIVES: Pancreatic endocrine tumors (PETs) have variable prognoses, and predictors of survival are lacking. PETs can be difficult to distinguish histologically from aggressive pancreatic neoplasms such as acinar cell carcinoma. Telomerase is a ribonuclear protein that maintains the length of the telomere and induces cell immortality. Telomerase is present in 95% of pancreatic adenocarcinoma and is associated with aggressive tumor behavior. Our aim is to determine telomerase activity in PETs and investigate its potential role as a prognostic indicator. METHODS: Telomerase detection using the telomeric repeat amplification protocol was performed on frozen surgical archived pancreatic endocrine tissue from 30 patients with PETs identified by light microscopy (hematoxylin-eosin stain). All results were confirmed with internal controls. A patient's survival was measured from the time of surgery. Acinar cell differentiation (presence of zymogen granules) was determined by electron microscopy. Follow-up data were acquired via telephone interview, medical record review, and death certificates. RESULTS: Three of 30 PETs diagnosed by light microscopy were telomerase positive: three were considered nonfunctional, and two of these three patients had extrapancreatic disease. All three telomerase-positive cases were reclassified as either acinar cell carcinoma (two cases) or mixed acinar-endocrine cell carcinoma (one case). All three patients (mean age = 63 yr) died from tumor progression within 2 yr of surgery (mean = 1.6 yr +/- 0.5 SD). The remaining PETs were telomerase negative: 13 insulinomas, four nonfunctional, two sporadic glucagonomas, one gastrinoma, one vipoma, one carcinoidlike PET, and five PETs from three patients with multiple endocrine neoplasm syndrome type I and two patients with von Hippel-Lindau syndrome. Excluding insulinomas, 12 of 14 patients with telomerase-negative PETs had extrapancreatic disease. Nevertheless, Kaplan-Meier survival estimates for these 12 patients were significantly longer than for patients with telomerase-positive acinar cell carcinoma (92% vs 0% at 2 yr, p = 0.001, log rank test). The survival of all telomerase-negative PETs (n = 27) was significantly longer than that of the patients with telomerase-positive acinar cell carcinoma (93% vs 0% at 2 yr, p = 0.0001). CONCLUSIONS: Telomerase activity helps to identify acinar cell carcinomas that histologically resemble PETs, which accounts for the poor prognosis demonstrated in these patients. The absence of telomerase activity in most PETs may be responsible for their indolent clinical course. Telomerase may identify potentially progressive tumors, such as acinar cell carcinoma, and may be useful in selecting patients for more aggressive treatment.

Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol 2002;20:2633–2642.

PURPOSE: In some organs (eg, the lung), endocrine tumors are classified on the basis of mitotic rate and necrosis. The purpose of this study was to evaluate prognostic factors in pancreatic endocrine neoplasms recently treated at a single institution. PATIENTS AND METHODS: In 136 patients undergoing surgery from 1979 to 1998, the influence on disease-free survival (DFS) and disease-specific survival (DSS) of tumor size, mitotic rate, vascular invasion, necrosis, metastases, and nuclear grade was determined. Cases were further grouped according to an existing proposed classification system and then regrouped on the basis of mitotic rate (< 2 mitoses per 50 high-power fields v higher) and necrosis (present or absent) into low- and intermediate-grade groups. RESULTS: Correlations with DFS and DSS in univariate analysis included < or = 2 mitoses per 50 high-power fields (P =.001, P =.002), vascular invasion (P =.02, P =.04), size < or = 2 cm (P =.01, P =.05), metastases (P =.0002, P =.07), necrosis (P =.002, P =.16), and nuclear grade (P =.04, P =.33), respectively. By multivariate analysis, for DFS, tumor necrosis and presence of metastases retained significance (P =.01, P =.04, respectively). For DSS, only mitotic rate was a prognostic factor (P =.02). Among the 18 macroadenomas, eight borderline tumors, and 48 low-grade carcinomas, there was no significant difference in DSS between any groups (P =.3). However, in evaluating our newly proposed groups, the differences in DFS and DSS between low- and intermediate-grade groups were highly significant (P =.0007, P =.006, respectively). CONCLUSION: Pancreatic endocrine neoplasms exhibit a spectrum of biologic behavior, and the proposed benign (macroadenoma) and borderline groups contain potentially aggressive tumors. An alternative system based on mitotic rate and necrosis correlates strongly with survival without specifically designating any group as benign.

Predictive factors associated with long-term survival in patients with neuroendocrine tumors of the pancreas. Ann Surg Oncol 2002;9:855–862.

BACKGROUND: Neuroendocrine tumors of the pancreas are rare tumors. We identified predictive factors that are associated with long-term survival (> or=5 years). METHODS: Fifty patients with a diagnosis of neuroendocrine tumors of the pancreas were retrospectively evaluated. The following factors were evaluated for disease-specific mortality: age, sex, primary tumor location, functional status, type of primary tumor treatment, presence or absence of liver metastases, timing of liver metastases occurrence, and type of liver metastases treatment. Aggressive treatment of the liver metastases included surgery, chemoembolization, or intrahepatic arterial infusion chemotherapy. RESULTS: Twenty-three patients (47%) had tumor located in the head of the pancreas, and 29 patients (58%) had nonfunctioning tumor. Thirty-nine patients (78%) had liver metastases. The median follow-up for the entire group was 35 months (range,.76-206 months). The median survival for the entire group was 40 months, and the overall 1-, 2-, and 5-year survival rates were 84%, 69%, and 36%, respectively. Factors that had a significant favorable effect on survival included curative resection of the primary tumor, metachronous liver metastases, absence of liver metastases, and aggressive treatment of the liver metastases. CONCLUSIONS: Definitive surgical resection of the primary tumor, absence of liver metastases, metachronous liver metastases, and aggressive treatment of the liver metastases were predictors of long-term survival in patients with neuroendocrine tumors of the pancreas.

Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma. Am J Surg Pathol 2001;25:602–609.

The dominantly inherited von Hippel-Lindau disease is characterized by clear cell neoplasms in various organs including the kidney and pancreas. Determination of primary versus metastatic lesion in this setting can be a diagnostic dilemma. The authors present five cases of clear cell endocrine pancreatic tumor (EPT) closely mimicking renal cell carcinomas in five patients with a family history or histologic evidence of von Hippel-Lindau disease. In fact, two of these tumors were confused with metastatic renal cell carcinoma by fine-needle aspiration. All five tumors had a component of clear cells arranged in nests, cords, and tubules with central hemorrhage separated by thin-wall vessels resembling renal cell carcinoma. However, these tumors also exhibited cords and festoons and a gyriform pattern suggestive of an endocrine neoplasm, and expressed chromogranin and synaptophysin. Vascular invasion was identified in four tumors, one of which metastasized. The concurrent primary renal cell carcinomas and the multicentric microcystic adenomas found in three patients did not show reactivity for the neuroendocrine markers. Focal clear cell change was noted in only one of 29 endocrine pancreatic tumors arising in patients without von Hippel-Lindau disease. Eleven metastatic renal cell carcinomas in the pancreas did not show immunoreactivity with the endocrine markers. Clear cell EPTs closely mimicking renal cell carcinoma are distinctive neoplasms of von Hippel-Lindau disease. In contrast to clear cell EPT, metastatic renal cell carcinoma does not express neuroendocrine markers and lacks neurosecretory granules by electron microscopy. Von Hippel-Lindau disease should be strongly suspected in patients with renal cell carcinoma, clear cell EPT, and multifocal microcystic serous adenomas.