The transformation of a nonfunctioning islet cell tumor of the pancreas into a proinsulinoma under conditions of lung metastasis.

We herein report the first case of a nonfunctioning islet cell tumor that transformed into a proinsulinoma during the process of metastasis to the lungs. This phenomenon was confirmed in a 69-year-old woman with an advanced pancreatic islet cell tumor and multiple liver metastases who later developed multiple lung metastases. She underwent pancreatic resection followed by the administration of chemotherapy and survived for seven years. Although the patient initially had hyperglycemia due to diabetes mellitus, she conversely began to manifest hypoglycemic attacks 63 months postoperatively with the concomitant development of multiple lung metastases. An autopsy revealed that only the tumor in the lungs produced proinsulin; no other hormones were detected.

Characterization of neuroendocrine tumors of the pancreas by real-time quantitative polymerase chain reaction. A methodological approach.

The aim of this study was to assess the suitability of using real-time quantitative PCR (RT-qPCR) to characterize neuroendocrine (NE) tumors of the pancreas. For a series of tumors, we evaluated several genes of interest, and the data were matched with the "classical" immunohistochemical (IHC) features. In 21 cases, we extracted RNA from formalin-fixed paraffin-embedded (FFPE) blocks, and in nine cases, we also extracted RNA from fresh-frozen tissue. The RT-qPCR procedure was performed using two sets of customized arrays. The test using the first set, covering 96 genes of interest, was focused on assessing the feasibility of the procedure, and the results were used to select 18 genes indicative of NE differentiation, clinical behavior, and therapeutic responsiveness for use in the second set of arrays. Threshold cycle (Ct) values were used to calculate the fold-changes in gene expression using the 2-∆∆Ct method. Statistical procedures were used to analyze the results, which were matched with the IHC and follow-up data. Material from fresh-frozen samples performed better in terms of the level of amplification, but acceptable and concordant results were also obtained from FFPE samples. In addition, high concordance was observed between the mRNA and protein expression levels of somatostatin receptor type 2A (R = 0.52, p = 0.016). Genes associated with NE differentiation, as well as the gastrin-releasing peptide receptor and O-6-methylguanine-DNA methyltransferase genes, were underexpressed, whereas angiogenesis-associated markers (CDH13 and SLIT2) were overexpressed in tissues with malignant behavior. The RT-qPCR procedure is practical and feasible in economic terms for the characterization of NE tumors of the pancreas and can complement morphological and IHC-based evaluations. Thus, the results of the RT-qPCR procedure might offer an objective basis for therapeutic choices.

Prognostic relevance of survivin in pancreatic endocrine tumors.

BACKGROUND: Better prognostic markers are needed for pancreatic endocrine tumors. Survivin is an apoptosis inhibitor that is suggested to have a negative prognostic impact in several tumor types. Contradictory data exist, especially regarding the significance of a nuclear versus cytoplasmic location of survivin. The prognostic relevance of nuclear and cytoplasmic survivin expression in pancreatic endocrine tumors-controlled for the tumor Ki-67 index, World Health Organization classification, and TNM stage-was investigated. METHODS: A total of 111 patients treated at a tertiary referral center were retrospectively evaluated. Clinical data were gathered from medical records. Immunohistochemistry for survivin and Ki-67 was performed on paraffin-embedded tissue. Univariate and multivariate Cox analyses were performed. RESULTS: Patients with tumors that had <5% survivin-positive nuclei had a mean survival of 225 months [95% confidence interval (CI) 168-281]. The corresponding figure for patients with 5 to 50% survivin-positive tumor cell nuclei was 101 months [95% CI 61-140; hazard ratio (HR) 2.4; P < 0.01) and with >50% survivin-positive nuclei 47 months (95% CI 24-71; HR 4.9; P < 0.001). Nuclear survivin expression in >50% of the tumor cells was an independent marker of a poor prognosis (HR 5.7; P < 0.01). Cytoplasmic survivin was not a significant prognostic factor in the multivariate analysis (HR 0.94; P = 0.90). CONCLUSIONS: High expression of nuclear survivin is a significant marker of a poor prognosis in patients with a pancreatic endocrine tumor.

Proposed histopathologic grading system derived from a study of KIT and CK19 expression in pancreatic endocrine neoplasm.

Predicting the biologic behavior of pancreatic endocrine neoplasm in the absence of local invasion or metastasis is difficult. We recently proposed an immunohistochemical classification system based on a combination of KIT and CK19 expression: low risk (KIT-/CK19-), intermediate risk (KIT-/CK19+), and high risk (KIT+/CK19+). In the current study, we sought histopathologic features that correlated with the immunohistochemical categories and that could be used in predicting tumor behavior. We assessed histologic findings of 97 pancreatic endocrine neoplasm that had been classified into 3 risk groups based on KIT/CK19 expression. Clinicopathologic associations with prognosis were evaluated using Cox proportional hazards regression models. Tumor size, mitoses, infiltrative border, extrapancreatic extension, perineural invasion, and presence of amyloid were significantly different among the 3 risk groups, and tumor necrosis approached statistical significance as well (P = .089). A scoring system using mitoses, necrosis, and tumor border was developed as follows: mitosis: 0 (0/50 high-power field), 1 (1-3/50 high-power field), and 2 (≥4/50 high-power field); necrosis: 0 (absent) and 1 (present); tumor border: 0 (noninfiltrating) and 1 (infiltrating), giving a possible histology score of 0 to 4. Although there was an overall difference in disease-specific survival among the 4 histology scores (P < .001), there was not a statistically significant difference between patients with scores of 0 and 1 or between patients with scores of 3 and 4. Therefore, a 3-tied grading system was developed by combining score 0 and 1 tumors as grade 1, score 2 tumors as grade 2, and score 3 and 4 tumors as grade 3. There was a significant difference in survival, tumor metastasis, tumor recurrence, and functioning status among the 3 grades. By analyzing histopathologic features in KIT/CK19 risk groups, we developed a 3-tiered histopathologic grading system using reproducible parameters (mitoses, tumor necrosis, and infiltrative border) that are easy to apply in practice.

Diagnostic approach to pancreatic tumors with the specimens of endoscopic ultrasound-guided fine needle aspiration.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has enabled clinicians to histologically diagnose pancreatic tumors. However, EUS-FNA specimens often result in tiny fragmented tissues, so auxiliary utilities are necessary. Using immunostaining of CK7, CDX2, neuroendocrine markers and KRAS mutation analysis, we examined 57 FNA cell block sections and 61 surgically-resected specimens (25 invasive ductal carcinomas, 25 endocrine tumors, and 11 acinar cell tumors). In the majority of the matched pairs, the diagnoses between EUS-FNA and surgical specimens were concordant using the following criteria: neuroendocrine markers negative, CK7 positive, and mutated KRAS gene for invasive ductal carcinomas; neuroendocrine markers diffusely positive, CK7 and CDX2 negative, and wild-type KRAS gene for well-differentiated endocrine tumors; and neuroendocrine markers no more than focal positive, CK7 and CDX2 with various staining patterns, and wild-type KRAS gene for acinar cell carcinomas. Expression of CK7 and/or CDX2 in addition to KRAS mutations were occasionally seen in endocrine carcinomas, but not in well-differentiated endocrine tumors, suggesting that ductal differentiation in an endocrine tumor may be a predictor of aggressive disease. The usefulness of these markers was confirmed using 13 additional pancreatic tumors, prospectively. Although minimal in selection, these markers are helpful in making diagnosis from EUS-FNA specimens of the major pancreatic tumors.

PAX8 Expression in well-differentiated pancreatic endocrine tumors: correlation with clinicopathologic features and comparison with gastrointestinal and pulmonary carcinoid tumors.

PAX (paired box) genes encode a family of transcription factors that regulate organogenesis and cell-lineage specification in multiple organ systems. In the pancreas, PAX proteins play a critical role in islet cell differentiation. We recently observed that islet cells show strong, diffuse staining for PAX8 by immunohistochemistry. However, PAX8 expression has not previously been examined in pancreatic endocrine tumors (PETs). The purpose of this study was to evaluate PAX8 expression in PETs, and to correlate expression with clinical and pathologic features and behavior. PAX8 expression in other well-differentiated neuroendocrine tumors (WDNETs) was also studied. In total, 190 tumors were evaluated: 156 primary WDNETs (63 PETs, 31 ileal, 5 duodenal, 5 gastric, 19 appendiceal, 13 rectal, and 20 pulmonary carcinoid tumors) and 34 liver metastases (18 PETs and 16 ileal carcinoid tumors). PAX8 was positive in 42/63 (67%) primary PETs. Expression of PAX8 was significantly associated with WHO category 1.1 ("benign" behavior) compared with category 1.2 (uncertain behavior) or 2 (well-differentiated endocrine carcinoma) (positive in 100%, 64%, and 52% of tumors, respectively; P<0.05). PAX8-positive PETs were also significantly smaller and more often clinically functional; PAX8-negative tumors were more frequently associated with liver metastases. PAX8 expression was not associated with patient age, gender, MIB1 index, or lymph node metastases. PAX8 expression was detected in 0/20 (0%) pulmonary, 1/5 (20%) gastric, 5/5 (100%) duodenal, 0/31 (0%) ileal, 4/19 (21%) appendiceal, and 11/13 (85%) rectal carcinoid tumors. Among the liver metastases, PAX8 was positive in 9/18 (50%) metastatic PETs compared with 0/16 (0%) metastatic ileal carcinoid tumors. In summary, PAX8 is expressed in normal pancreatic islet cells and in a high proportion of primary and metastatic PETs. In the GI tract, PAX8 is positive in the majority of duodenal and rectal carcinoid tumors, and in a minor subset of appendiceal and gastric carcinoids. PAX8 expression is absent in ileal and pulmonary carcinoid tumors. PAX8 immunostaining may be helpful in determining the primary site for a WDNET metastatic to the liver, as ileal (PAX8 negative) and pancreatic (PAX8 positive) tumors most often present as a metastasis from an occult primary. PAX8 may also be a prognostic marker in PETs, as loss of expression is associated with malignant behavior.

Pancreatic acinar cell carcinomas with prominent ductal differentiation: Mixed acinar ductal carcinoma and mixed acinar endocrine ductal carcinoma.

BACKGROUND: Pancreatic acinar cell carcinomas (ACCs) are clinically and pathologically distinct from pancreatic ductal adenocarcinomas (PDAs). Whereas endocrine differentiation has been well shown in ACCs, significant ductal components are rare. This paper reviews the clinicopathologic features of a series of ACCs with prominent ductal differentiation. DESIGN: Cases of pancreatic ACCs with significant ductal differentiation were identified in the surgical pathology databases of 2 academic centers. Patient clinical information, gross and histologic features, and histochemical and immunohistochemical (IHC) results were recorded. Cases were tested for KRAS2 mutations. RESULTS: Eleven cases were identified (10 men and 1 woman; age range 52 to 79 y). Four patients presented with jaundice. At last follow-up, 7 patients died of disease and 2 others had recurrences. Tumors measured between 2 and 5.5 cm and were ill-defined, nodular, and multilobulated. Ten were located in the head of the pancreas. All but 2 exhibited extrapancreatic invasion. All cases showed significant evidence of both acinar and ductal differentiation, estimated to be at least 25% of the neoplastic cells, and 3 cases in addition had endocrine differentiation in more than 25% of cells. Five cases were predominately acinar with intracellular and sometimes extracellular mucin ("mucinous acinar cell carcinoma" pattern). Six cases seemed more mixed with areas recapitulating typical PDAs whereas the other portions of the tumors seemed akin to typical acinar cell carcinomas ("combined acinar and ductal" pattern). IHC positive staining results were as: trypsin (92%), chymotrypsin (92%), monoclonal carcinoembryonic antigen (100%), CK19 (100%), B72.3 (73%), CA19.9 (73%), CD56 (18%), synaptophysin (36%), and chromogranin (36%). One case showed p53 over-expression aznd none showed DPC4/Smad4 loss. Two cases had KRAS2 mutations. CONCLUSION: Despite the early embryologic divergence of acinar and ductal cell lineages, rare pancreatic tumors have both acinar and ductal differentiation, usually predominantly the former. The clinical course is highly aggressive.

Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor.

OBJECTIVE: The goal of the study was to investigate the genetic and molecular basis of a novel syndrome of marked hyperglucagonemia and pancreatic alpha cell hyperplasia without glucagonoma syndrome. METHODS: The glucagon receptor (GCGR) gene and the glucagon gene were sequenced in a patient with hyperglucagonemia and pancreatic alpha cell hyperplasia without glucagonoma syndrome. Enhanced green fluorescent protein-conjugated wild type (WT) and mutant GCGR were used to characterize the functions of the mutant GCGR. RESULTS: The glucagon gene sequence was normal, but the GCGR sequencing uncovered a homozygous missense mutation, c.256C>T, p.P86S in the extracellular domain of GCGR. When expressed in human embryonic kidney 293 cells, GCGR P86S localized to the plasma membrane but bound 96% less radiolabeled glucagon than WT GCGR. The median effective concentration of glucagon-induced cyclic adenosine monophosphate production was 24 nmol/L for GCGR P86S but 2.4 nmol/L for WT GCGR. The patient's alpha cells also express glucagonlike peptide 1 and pancreatic polypeptide. CONCLUSIONS: We hereby report the first homozygous missense mutation in the human GCGR, which is associated with alpha cell hyperplasia and hyperglucagonemia. This mutation lowers the receptor's affinity to glucagon and decreases cyclic adenosine monophosphate production with physiological concentrations of glucagon. Thus, the P86S mutation in GCGR likely causes alpha cell hyperplasia and hyperglucagonemia.

Neuroendocrine tumors of the pancreas.

Pancreatic endocrine tumors are rare neoplasms accounting for less than 5% of pancreatic malignancies. They are broadly classified into either functioning tumors (insulinomas, gastrinomas, glucagonomas, VIPomas, and somatostatinomas) or nonfunctioning tumors. The diagnosis of these tumors is difficult and requires a careful history and examination combined with laboratory tests and radiologic imaging. Signs and symptoms are usually related to hormone hypersecretion in the case of functioning tumors and to tumor size or metastases with nonfunctioning tumors. Surgical resection remains the treatment of choice even in the face of metastatic disease. Further development of novel diagnostic and treatment modalities offers potential to greatly improve quality of life and prolong disease-free survival for patients with pancreatic endocrine tumors.

An unusual mixed tumor of the pancreas: sonographic and MDCT features.

CONTEXT: Mixed tumors of the pancreas are exceedingly rare. CASE REPORT: We herein report on a 54-year-old female who presented with an enlarging cystic lesion in the head of the pancreas. Right upper quadrant ultrasound and multidetector-row CT scan showed a well-defined unilocular cystic tumor located in the head of the pancreas and surrounded, in part, by a hypervascular solid mass. CONCLUSION: Although mixed exocrine/endocrine pancreatic tumors have been described previously, to the best of our knowledge, this is the first case of a pancreatic mixed intraductal papillary mucinous neoplasm/endocrine tumor with illustration of its ultrasound and CT features. Moreover, the importance of preoperative analysis of imaging features in the assessment of pancreatic neoplasms is discussed.

Improved histologic and clinicopathologic criteria for prognostic evaluation of pancreatic endocrine tumors.

Currently used histopathologic criteria for the diagnosis of pancreatic endocrine tumors are still under discussion as far as to their capacity to identify prognostically different tumor subsets, which are potentially helpful for patient management. A recently developed TNM staging system and a variety of proposed histologic and clinicopathologic parameters still need to be fully validated. One hundred fifty-five pancreatic endocrine tumors encompassing all the main histologic types and stages, operated with intention to cure and then followed up for a median 126 months, were carefully investigated histologically to identify prognostically informative parameters at univariable, bivariable, and multivariable analysis. Ki67 index, mitotic rate, neuroinvasion with or without vascular, peritumoral or stromal infiltrative patterns, as well as tumor size, and association with endocrine syndromes other than insulinoma proved effective in predicting recurrence and disease-specific death among well-differentiated tumors. Poorly differentiated histologic features, more than 10 mitoses/10 high power fields, and necrosis were helpful in the identification of high-grade cancers with an invariably poor prognosis. The TNM system proved to be highly predictive of patient outcome and easy to combine with histologic and clinicopathologic parameters to classify pancreatic endocrine tumors into groups of increasing malignant potential.

Neuroendocrine tumors of the pancreas.

The neuroendocrine tumors (NET) of the pancreas are very rare lesions with frequency of about 3 to 10 per 1 000 000 inhabitants. The neuroendocrine tumors composes a heterogeneous group of tumors. The gastro-entero-pancreatic tumors (GEP) constitute 70% of all NET and 2% of all digestive system tumors. There have been several attempts to classify those lesions and since 2000 exists WHO classification which divides NET according to malignancy and histologic structure. The most often NET of the pancreas are insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma. There is a recommendation to assay hormonal activity, measure concentration of specific peptides, biogenic amines and hormones produced by NET cells to establish diagnosis. Those tests are useful in monitoring treatment and in prognostication course of the disease. Imaging methods especially useful in localization GEP-NET are: ultrasound (US), endoscopic ultrasound (EUS), somatostatin receptor scintigraphy (SRS), computer tomography (CT), magnetic resonance (MR) and angiography. The most sensitive method in preoperative diagnosis seems to be EUS or less accessible intra ductal ultrasonography (IDUS). Surgical treatment depends on progression of disease as well as on localization of tumor and consists in both radical methods and palliative operations. The gold standard in pharmacological treatment are somatostatin analogs which can induce long-term remission even in inoperable lesions. Although NET of pancreas are very rare. they are still important diagnostic and therapeutic problem and requires interdisciplinary co-operation. The neuroendocrine tumors should be treated in centers with highest rank of references.

Hypoglycemia associated with the production of insulin-like growth factor II in a pancreatic islet cell tumor: a case report.

An insulinoma is characterized by endogenous hyperinsulinemia and hypoglycemia. However, it has been reported that insulinomas with normal levels of plasma insulin and a normal insulin to glucose ratio occur in patients with hypoglycemia. Although overproduction of Insulin-like growth factor II (IGF-II) by non-islet cell tumors such as large mesenchymal tumors, can cause hypoglycemia, no cases of circulating plasma IGF-II from an islet cell tumor contributing to hypoglycemia have been reported. We report here a rare case of a pancreatic islet tumor in a patient with hypoglycemia that was associated with increased plasma IGF-II, which returned to normal after tumor resection.

Cell adhesion molecule 1 is a novel pancreatic-islet cell adhesion molecule that mediates nerve-islet cell interactions.

BACKGROUND & AIMS: Cell adhesion molecule 1 (CADM1), mediates nerve-mast cell attachment and communication through homophilic binding. An immunohistochemical screen showed that CADM1 is expressed in pancreatic islets. Here, we determined the cell types expressing CADM1 and examined its role in nerve-islet cell interactions. METHODS: Immunohistochemistry and double-staining immunofluorescence were performed on murine and human pancreases and on islet cell tumors (ICTs). alphaTC6 cells, a murine alpha cell line, were cultured on neurite networks of superior cervical ganglia. Neurite-alphaTC6 cell attachment and communication were examined after nerves were activated specifically by scorpion venom. RESULTS: CADM1 was expressed on the plasma membrane in all 4 major types of islet cells, alpha, beta, D, and pancreatic polypeptide in human beings, but primarily in alpha cells in mice. In cocultures, alphaTC6 cell to neurite attachment was inhibited dose-dependently by an anti-CADM1 function-blocking antibody. In response to scorpion venom-evoked nerve activation, 36% of the alphaTC6 cells mobilized Ca(2+), and introduction of a CADM1-targeting small interfering RNA reduced the fraction of responding cells to 7%. In 21 human ICTs, CADM1 was present in the plasma membrane of 7, and the others were negative for CADM1. Six of the CADM1-expressing tumors were functional hormonally, whereas all but 2 of the CADM1-negative tumors were nonfunctional (P = .0032). CONCLUSIONS: CADM1 is a novel islet cell adhesion molecule mediating nerve-islet cell interactions. The strong correlation between CADM1 expression and hormonally functional phenotypes suggests that CADM1 is involved in hormone secretion from ICTs.

Usefulness of S100P in diagnosis of adenocarcinoma of pancreas on fine-needle aspiration biopsy specimens.

Even though the cytologic criteria for pancreatic ductal adenocarcinoma (PDA) on fine-needle aspiration biopsy (FNAB) specimens have been well defined, a diagnostic challenge is still present. We immunohistochemically evaluated the diagnostic value of S100P on cell-block and/or smear preparations in 58 cases of FNAB specimens of the pancreas. The 58 cases were divided into 4 groups: 1, 32 cases of PDA; 2, 6 cases with an atypical or "suspicious" diagnosis; 3, 14 cases of benign or reactive ductal epithelium; and 4, 6 cases of endocrine tumor. Positive immunoreactivity for S100P was observed in all cases in groups 1 and 2, whereas only 1 of 14 cases in group 3 was positive for S100P. All cases in group 4 were negative for S100P. S100P is a sensitive and specific marker for the detection of PDA on FNAB specimens on cell-block and smear preparations.

Mixed ductal-endocrine carcinoma derived from intraductal papillary mucinous neoplasm (IPMN) of the pancreas identified by human telomerase reverse transcriptase (hTERT) expression.

We report a case of mixed ductal-endocrine carcinoma derived from intraductal papillary mucinous neoplasm (IPMN) of the pancreas. The tumor presented intermingled exocrine and endocrine carcinomatous components and expressed intense human telomerase reverse transcriptase (hTERT), further confirming the malignant features. This pathologically unique tumor is the first case of mixed ductal-endocrine carcinoma derived from pancreatic IPMN and telomerase activation could play a potential role in the neoplastic progression of mixed ductal-endocrine carcinomas of the pancreas.

[Case of pancreatic endocrine tumor associated with Cushing's syndrome].

A 78-year-old woman was admitted complaining of edema of the bilateral lower extremities and face. Computed tomography (CT) and ultrasonography (US) of her abdomen revealed a pancreatic tumor and multiple liver metastases. After admission, hypokalemia and muscle weakness and edema of the bilateral lower extremities rapidly worsened. The diagnosis of Cushing's syndrome was established based on clinical and biochemical data and endocrine studies. We thought that the primary tumor was a pancreatic endocrine tumor based on the liver tumor biopsy findings, and that the pancreatic tumor and liver metastatic tumors were ectopic ACTH-producing tumors. A case of pancreatic endocrine tumor associated with Cushing's syndrome is relatively rare. We summarize previous reports.

Claudin expression in pancreatic endocrine tumors as compared with ductal adenocarcinomas.

Altered expression of recently described claudins (CLDNs) as members of tight junction (TJ) transmembrane proteins was noted in several malignancies. We aimed to analyze protein and messenger RNA (mRNA) expressions of different CLDNs in human pancreatic endocrine tumors (PET) and ductal adenocarcinomas. A total of 45 formalin-fixed, paraffin-embedded samples were studied. Immunohistochemistry and real-time reverse transcriptase polymerase chain reaction analysis were carried out for quantification of CLDN 1, -2, -3, -4, and -7 expressions. Normal acini and ducts showed strong CLDNs 1, -3, -4, and -7 and scattered CLDN 2 protein expressions, while Langerhans islands revealed only CLDN 3 and -7 expressions. CLDN 2 expression was found in the half of ductal adenocarcinomas, while the vast majority of endocrine tumors were negative. CLDN 1, -4, and -7 immunohistochemistry was positive in all adenocarcinomas, whereas endocrine tumors were completely negative for CLDNs 1 and -4. CLDN 3 and -7 proteins were detected in all endocrine tumors, while CLDN 3 in ductal adenocarcinomas was negative. The mRNA expression of CLDNs showed differences between endocrine tumors and ductal adenocarcinomas, similar as found for protein expression. Our findings support that PET and ductal carcinomas are specifically characterized by different expression pattern of CLDNs. High expressions of CLDN 3 in endocrine tumors and CLDN 4 in ductal carcinomas might attract them as targets for adjuvant therapy.

Prognostic and biological significance of cytokeratin 19 in pancreatic endocrine tumours.

AIM: The prognosis of well-differentiated pancreatic endocrine tumours (PETs) is difficult to establish on a histological basis. The expression of cytokeratin (CK19) has recently been proposed as an indicator of unfavourable outcome. However, this finding still needs to be verified and to be compared with more frequently used prognosticators such as proliferative indices, vascular and/or perineural invasion. The aim of this study was to evaluate the prognostic value of CK19 expression in PETs. METHODS AND RESULTS: One hundred and forty-five PETs were studied using two different anti-CK19 monoclonal antibodies (BA17 and RCK108). The results were statistically compared with proliferation markers, vascular and perineural invasion and the presence of metastases. On univariate analysis, CK19 immunoreactivity correlated with prognosis only when it was detected with the RCK108 antibody and only in the whole group of PETs and in insulinomas. Conversely, it did not predict survival in non-functioning neoplasms. Ki67 index, mitotic count, vascular and perineural invasion were all statistically correlated with prognosis. On multivariate analysis, only the Ki67 index and metastases were independent prognosticators. CONCLUSIONS: CK19 expression correlates with patient survival only when detected with the RCK108 antibody and mainly in insulinomas. Ki67 index and metastases represent the only two independent predictors of survival.