Distribution of somatostatin in pancreatic ductal adenocarcinoma remodels the normal pattern of the protein during foetal pancreatic development: an immunohistochemical analysis

Abstract Aim: To determine the immunoreactivity of somatostatin during the development of the human fetal pancreas and pancreatic ductal adenocarcinoma, given that, somatostatin-positive cells were demonstrated either into its embryonic anlage or into pancreatic cancer. Methods: Tissue sections from 15 pancreatic fetal specimens, and an equal number of ductal adenocarcinoma specimens were assessed. Results: The density of positive cells in the primitive exocrine ductal epithelium and endocrine epithelium was significantly different from the relevant density in the neoplastic pancreatic tissue of mixed (ductal-endocrine) and pure ductal type (P1=0.021 P2=0.001, P3<0.0001, P4=0.003 respectively). The above values were estimated from the 8th to 10th week. There was no significant difference in the density of positive cells in the mantle zone of the islets from the 13th to the 24th week, and the neoplastic tissue of mixed (P5=0.16) and pure ductal type (P6=0.65). Conclusion: The immunostaining for somatostatin identifies a subgroup of pancreatic ductal adenocarcinomas with a neuroendocrine component, (initially considered as pure ductal tumors), and mixed ductal and neuroendocrine tumors. This pattern of expression in neoplasms recapitulates the normal pattern during the embryonal development of the organ, raising the question of therapeutic efficacy of somatostatin and analogues as monotherapy in pancreatic cancer management.     

Biomarkers in Diagnosis of pancreatic carcinoma in fine-needle aspirates

This study was undertaken to determine whether recently identified proteins could be translated to clinical practice as markers to distinguish pancreatic adenocarcinoma from chronic pancreatitis on fine-needle aspirate (FNA) samples. Resected pancreatic tissue sections (n = 40) and FNA samples (n = 65) were stained for clusterin-beta, MUC4, survivin, and mesothelin. For each biomarker, the staining patterns in adenocarcinoma and in reactive ductal epithelium were evaluated and compared. Clusterin-beta stained reactive ductal epithelium significantly more frequently than pancreatic adenocarcinoma (P < .001). In comparison, MUC4 and mesothelin were expressed more frequently in pancreatic adenocarcinoma on tissue sections. Positive staining for MUC4 (91% vs 0%; P < .001) and mesothelin (62% vs 0%; P = .01) and absence of staining for clusterin-beta (90% vs 7%; P < .001) were noted significantly more frequently in adenocarcinoma cells than in reactive cells in FNA samples. Clusterin-beta and MUC4 can help distinguish reactive ductal epithelial cells from the cells of pancreatic adenocarcinoma in FNA samples.     

Hepatocyte growth factor and Met receptor expression in human pancreatic carcinogenesis.

We have used immunohistochemistry to evaluate the clinicopathological significance of hepatocyte growth factor (HGF) and Met/HGF receptor expression in ductal lesions of 46 human pancreata. Normal duct epithelium shows no significant immunoreactivity for either HGF or Met. Strong immunostaining for HGF was respectively demonstrated in hyperplastic and severely dysplastic epithelia in 35.5 and 40% of cases with such duct lesions, whereas 37% of ductal adenocarcinoma showed diffuse HGF immunostaining. Positive Met immunostaining was demonstrated in 58, 80, and 78%, respectively, of specimens demonstrating the above duct lesions. Patients with resectable ductal adenocarcinoma demonstrating diffuse Met immunostaining have a significantly longer survival than those with tumors showing negative/focal staining (19.7 versus 8.1 months at P = 0.026). In contrast, HGF immunoreactivity did not significantly correlate with the survival of the patients. The results suggest that HGF and Met expression may play significant bifunctional roles during human pancreatic ductal carcinogenesis and progression. Whereas an upregulation of Met receptor expression and HGF-Met interaction may have an important pathogenetic role during the early stages of neoplastic promotion, a lack or subsequent loss of Met expression in invasive adenocarcinoma appears to result in a more aggressive clinical behavior.     

Somatostatin type 2A receptor immunoreactivity in human pancreatic adenocarcinomas

Somatostatin and its analogs have been included in experimental treatment protocols for advanced pancreatic adenocarcinoma based on their known antisecretory and antiproliferative properties. Somatostatin receptor type 2 (sstr2A) mediates antiproliferative actions of somatostatin and has the strongest affinity to the therapeutically used somatostatin analog—octreotide. We investigated localization of sstr2A in 27 pancreatic adenocarcinomas in relation to tumor histological features and neuroendocrine differentiation confirmed by immunoreactivity for chromogranin A (CgA), chromogranin B (CgB), or somatostatin. Immunoreactivity for sstr2A generally coincided with tumor neuroendocrine differentiation demonstrated by staining for CgA and was present on the cell membranes of pancreatic islet cells and endocrine cells occasionally present in the wall of normal pancreatic ducts. Thirteen pancreatic adenocarcinomas contained cells immunoreactive for sstr2A in numbers ranging from occasional single cells, cell clusters, or carcinoma duct segments. In two cases, cells immunoreactive for sstr2A and CgA represented more than 30 and 10% of the total tumor cell population (case 1 and 15, respectively). Case 1 fulfills the diagnostic criteria of mixed ductal endocrine carcinoma. We conclude that immunohistochemical staining for a generic neuroendocrine marker such as CgA would facilitate identification of a subgroup of pancreatic adenocarcinomas expressing sstr2A receptors. Future studies need to evaluate the responsiveness of these tumors to somatostatin analogue treatment.     

Large duct type invasive adenocarcinoma of the pancreas with microcystic and papillary patterns: a potential microscopic mimic of non-invasive ductal neoplasia

A morphological variant of pancreatic ductal adenocarcinoma forming large ductal elements, large duct type ductal adenocarcinoma, is documented and its clinicopathological features are studied. These tumors may have microcystic and papillary growth patterns that closely mimic the non-invasive cystic and papillary pancreatic tumors such as: intraductal papillary-mucinous neoplasia, including the oncocytic variant, mucinous cystic neoplasms, and ducts involved by pancreatic intraepithelial neoplasia. In a review of 230 pancreatectomy specimens with ductal adenocarcinoma, 28 (8%) cases of large duct type ductal adenocarcinomas were identified according to following criteria: more than 50% of the tumor sections available for examination contained infiltrative ducts with a diameter larger than 0.5?mm or had a macroscopically identifiable microcystic pattern. Overall characteristics of large duct type ductal adenocarcinomas were not too different than those of conventional ductal adenocarcinomas, except that there was a slight female predominance in the former (F/M=2.3). The mean age was 67 (vs 63 in conventional ductal adenocarcinomas; P=0.015), and occurrence in the tail was slightly more common (40% vs 18% in conventional ductal adenocarcinomas; P=0.006). Grossly, cysts measuring up to 1?cm was noted in 10 cases. Microscopically, large duct type adenocarcinomas were characterized by irregularly distributed large ducts with jagged edges, lined by columnar mucinous cells often having deceptively bland cytological features and variable degrees of papillomatosis. Stromal desmoplasia had a hypercellular quality (morphologically distinct from ovarian-like stroma) in four cases, and had a myxoid quality in others. KRAS oncogene mutation was identified in 9 out of 11 cases. Median, 1-year and 2-year survival rates were 16 months, 77% and 30%, respectively, as opposed to 12 months, 52% and 30%, respectively, in conventional ductal adenocarcinoma. In conclusion, it should be recognized that, some (8%) pancreatic ductal adenocarcinomas exhibit a large duct pattern that may microscopically mimic non-invasive pancreatic tumors characterized by cystic and papillary patterns. They may be distinguished by the relatively smaller size of the cysts, irregularity of the duct contours, clustering of the ducts, presence of intraluminal neutrophils and granular debris, degree of cytological pleomorphism, and myxoid quality of the stroma. Clinical behavior appears to be slightly better than that of conventional ductal adenocarcinoma, which may be accounted by the well-differentiated nature of these tumors.     

Immunohistochemical validation of a novel epithelial and a novel stromal marker of pancreatic ductal adenocarcinoma identified by global expression microarrays: sea urchin fascin homolog and heat shock protein 47

We extended the results of a previous microarray analysis by immunohistochemical validation of differential protein expression in a series of 57 surgically resected infiltrating ductal pancreatic adenocarcinomas. Two representative genes were examined: sea urchin fascin homolog (overexpressed in both cell lines and primary tumors) and heat shock protein 47 (HSP47; overexpressed in primary tumors only). Protein expression also was evaluated in the precursor lesions of pancreatic cancer pancreatic intraepithelial neoplasia (PanIN), and normal ductal epithelium. Fascin expression was seen in the neoplastic cells of 54 (95%) of 57 ductal adenocarcinomas but not in 49 (94%) of 52 adjacent nonneoplastic epithelium. In the multistep pathogenesis of ductal adenocarcinomas, fascin expression seemed to be a late event, usually present in PanINs 2 and 3. HSP47 expression was almost universal and most intense in the ductal adenocarcinoma-associated stromal desmoplasia (57/57), although 37 cases (65%) also expressed HSP47 in the neoplastic epithelium. HSP47 expression was absent in the majority of nonneoplastic pancreata (46 [88%]). Fascin and HSP47 are novel tumor markers with potential diagnostic and therapeutic implications for pancreatic carcinoma. These results establish the usefulness of global expression platforms to identify novel tumor markers.     

Chromosomal instability in pancreatic ductal cells from patients with chronic pancreatitis and pancreatic adenocarcinoma

Pancreatic adenocarcinoma is a disease with high mortality for which chronic pancreatitis confers a markedly increased risk. We hypothesize that chromosome instability and genomic damage occur in pre-neoplastic pancreatic ductal epithelium, and that this damage may be related to oxidative stress. We used dual-color fluorescence in situ hybridization with centromere probes and locus-specific arm probes for chromosome arms 11q, 17p, and 18q to identify genomic instability in cultures of normal-appearing human pancreatic ductal epithelium from normal organ donor controls compared to patients with chronic pancreatitis or pancreatic adenocarcinoma. To examine early pancreatic tumorigenesis, we studied only normal-appearing pancreatic ductal cells adjacent to pancreatitis or carcinoma. We found that, compared to the finding in normal controls, chromosomal abnormalities are present in normal-appearing human pancreatic ductal epithelia obtained from patients with chronic pancreatitis or pancreatic adenocarcinoma. Furthermore, these chromosomal abnormalities could be induced in cultured pancreatic ductal epithelium from normal organ donors by chronic exposure to dilute hydrogen peroxide, suggesting that oxidative stress may contribute to the development of chromosomal instability in the pancreas. These results elucidate a potential mechanism linking chronic pancreatitis to pancreatic cancer and suggest that chromosomal instability may be an early event in the pathogenesis of pancreatic cancer.     

Clinicopathological correlates of pancreatic intraepithelial neoplasia: a comparative analysis of 82 cases with and 152 cases without pancreatic ductal adenocarcinoma.

Pancreatic intraepithelial neoplasia is often associated with pancreatic ductal adenocarcinoma and is presumed to be its precursor. It has been difficult to determine the frequency of these lesions because until recently, there was no consensus regarding the terminology and criteria for their grading. Here we compare the frequency and clinical correlates of pancreatic intraepithelial neoplasia in pancreata involved by ductal adenocarcinoma and in benign ones, using the criteria put forward recently. We evaluated pancreatectomy specimens from 82 patients with ductal adenocarcinoma and 152 patients who underwent pancreatectomy for reasons other than primary malignancy (trauma, pancreatitis, and metastatic tumor to pancreas) for the presence, grade, and number of foci of pancreatic intraepithelial neoplasia. Cases were graded by the highest grade of pancreatic intraepithelial neoplasia focus identified. An average of 5.3 sections of pancreas was available for evaluation (range, 1-28 sections). Overall, the frequency of pancreatic intraepithelial neoplasia lesions in ductal adenocarcinoma patients, including Grade 1A (mucinous duct lesions), was 82%, which was significantly higher than the one in benign pancreata -54%, P <.001. There was a progressive increase from normal pancreata to pancreatitis and to ductal adenocarcinoma in the frequency of overall pancreatic intraepithelial neoplasia lesions (16%, 60%, and 82%, respectively) and Grade 3 pancreatic intraepithelial neoplasia (0%, 4%, and 40%, respectively). In most instances, in any given case of higher-grade pancreatic intraepithelial neoplasia lesion, there were also several foci of lower grade lesions. The frequency of higher-grade pancreatic intraepithelial neoplasia lesions (2 and 3) in pancreata resected for ductal adenocarcinoma was 59%, significantly higher than in those without primary carcinoma (17%). This progressive increase in frequency of pancreatic intraepithelial neoplasia from incidental pancreatectomies (presumed to have a nonpathologic pancreas) to pancreatitis (considered a risk factor for carcinoma) and to ductal adenocarcinoma constitutes an indirect support for the precancerous role attributed to pancreatic intraepithelial neoplasia lesions. The relatively high absolute occurrence of pancreatic intraepithelial neoplasia Grade 1A (mucinous duct lesions) in benign conditions (43%) suggests that this group represents a combination of neoplastic and non-neoplastic lesions.     

Argyrophilic and hormone immunoreactive cells in normal and hyperplastic pancreatic ducts and exocrine pancreatic carcinoma

Summary Scattered argyrophil cells were present in normal, large, medium-sized and small pancreatic ducts (ductules). There was marked increase in argyrophil cells in ducts with hyperplastic epithelium. Argyrophil cells were also found in 67.7% of all exocrine pancreatic carcinomas. In a well differentiated group including cystadenocarcinoma, mucinous carcinoma and well differentiated ductal adenocarcinoma argyrophil cells were found in all cases examined. Using four antisera (against insulin, glucagon, somatostatin and gastrin), insulin, glucagon and somatostatin cells were identified in 2.65%, 0.001% and 1.2% of normal ducts, and 7.5%, 2.4% and 4.6% of ducts with hyperplastic epithelium respectively and were also greatly increased in numbers in the latter group. Immunoreactive cells were present in 66.7% of exocrine carcinomas. Cells reactive for insulin were found in 7/15 cases; glucagon in 6/15 cases; somatostatin in 5/15 cases and gastrin in 2/15 cases. Eight cases contained two or more than two types of immunoreactive cells. The presence of argyrophil and hormone immunoreactive cells in pancreatic ducts and carcinomas is indicative of the close developmental relationship between endocrine and exocrine parts of the pancreas. The inter-relationship of response in the different cell types following stimulus suggests that injury to a common precursor may be involved.     

Keratinocyte growth factor induces pancreatic ductal epithelial proliferation.

Keratinocyte growth factor (KGF) causes a proliferation of pancreatic ductal epithelial cells in adult rats after daily systemic administration for 1 to 2 weeks. Even before the proliferation of intralobular ducts is histologically evident, KGF also induces proliferating cell nuclear antigen expression within the ductal epithelium of intercalated, intralobular, and interlobular ducts. KGF also causes incorporation of 5-bromodeoxyuridine in ductal epithelial cells. Epithelial cell proliferation is histologically most prominent at the level of the intralobular ducts adjacent to and within the islets of Langerhans. Pancreatic ductal proliferation is not histologically apparent in rats sacrificed 7 to 10 days after the cessation of KGF administration. The pancreatic hormones insulin, glucagon, somatostatin, and pancreatic polypeptide are normally distributed within islets that demonstrate intrainsular ductal proliferation. The proliferating ductal epithelium does not show endocrine differentiation as evidenced by the lack of immunoreactivity for pancreatic hormones. KGF is a potent in vivo mitogen for pancreatic ductal epithelial cells.     

CD34+ fibrocytes in neoplastic and inflammatory pancreatic lesions

Besides its function as a matrix-producing cell, the CD34+ fibrocyte has been reported to be an antigen-presenting cell capable of priming naive T cells in situ. Therefore, it has been claimed that the CD34+ fibrocyte may play an important role in host response to tissue damage. The objective of the present study was to analyze the presence and distribution of CD34+ fibrocytes and smooth muscle actin (SMA) reactive myofibroblasts in relation to the underlying pancreatic disease. We investigated a total of 12 pancreatic adenocarcinomas, 7 endocrine tumors of the pancreas, and 8 cases of chronic pancreatitis; in 11 cases, normal pancreatic tissue was available. The stroma of normal pancreatic tissue harbored diffusely scattered CD34+ fibrocytes. Chronic pancreatitis was characterized by an increased number of stromal CD34+ fibrocytes paralleled by a gain of SMA reactive myofibroblasts which were not observed in the normal pancreatic stroma. The stroma of pancreatic ductal adenocarcinomas and endocrine tumors was devoid of CD34+ fibrocytes or showed at least a focal loss of this cell type, whereas SMA reactive myofibroblasts were detected in both endocrine tumors and adenocarcinomas. We conclude that detection of CD34+ fibrocytes may constitute an adjunctive tool in distinguishing chronic pancreatitis from ductal adenocarcinoma since the absence of this cell population strongly favors a neoplastic process. Moreover, CD34+ fibrocytes and myofibroblasts appear to be involved in stromal remodeling associated with chronic pancreatitis and ductal adenocarcinoma.     

Differential expression of the cell-adhesion molecule Nr-CAM in hyperplastic and neoplastic human pancreatic tissue

Nr-CAM is a member of the immunoglobulin superfamily of neural cell-adhesion molecules initially thought to be expressed mainly in the brain. Here we show the presence of Nr-CAM protein in normal human pancreas and characterize its expression in hyperplastic and neoplastic human pancreatic tissue. Nr-CAM is expressed on the cell surface in normal pancreatic acini with enhanced staining at cell-cell junctions, and weak or no surface staining is seen on normal ductal cells. Nr-CAM expression is markedly up-regulated in intraductal hyperplasia. Expression was well maintained in well or moderately differentiated carcinoma but was reduced or absent from most poorly differentiated tumors. In addition, 4 of 4 human pancreatic adenocarcinoma cell lines tested demonstrated little or no Nr-CAM expression. This differential regulation of Nr-CAM expression suggests that it may be involved in the pathogenesis and invasive/metastatic behavior of pancreatic cancers. HUM PATHOL 32:396-400.     

Histologic characteristics of pancreatic intraepithelial neoplasia associated with different pancreatic lesions

Pancreatic intraepithelial neoplasia (PanIN) has been found in association with pancreatic ductal adenocarcinoma, intraductal papillary-mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other pancreatic lesions, but the characteristics of PanINs associated with these lesions are not well characterized. In this study, 185 partial or total pancreatectomy specimens were collected, and 173 had complete slides for reviewed, which included 74 pancreatic ductal adenocarcinomas, 28 IPMNs, 7 mucinous cystic neoplasms, 44 other nonductal tumors, and 20 nontumorous lesions. Differences in grade, extent, and duct involvement among PanINs associated with different lesions were analyzed. Patients with PanINs were older than those without, regardless of associated tumor or lesions. No sex predilection was noted. PanINs were found in 89%, 96%, 86%, 64%, and 55% pancreata with ductal adenocarcinomas, IPMNs, mucinous cystic neoplasm, other nonductal tumors, and nontumorous lesions, respectively. PanIN 1 and 2 were commonly associated with all types of lesions, but high-grade PanIN 3 was more frequently associated with ductal adenocarcinomas. Ductal involvement of PanINs was more extensive in association with ductal adenocarcinomas than in any other types of pancreatic tumors or lesions. PanINs associated with pancreatic ductal adenocarcinomas affected both the main and branched ducts, whereas PanINs associated with other types of pancreatic tumors or lesions were mainly present in the branch ducts. No statistical differences were observed in distribution, extent, and grade of PanINs among IPMNs, mucinous cystic neoplasms, other nonductal tumors, and nontumorous lesions. Our study demonstrated a high concurrence between PanINs and other precancerous lesions and histologic features of PanINs associated with different pancreatic diseases.     

Utility of pVHL,maspin, IMP3, S100P and Ki67 in the distinction of autoimmune pancreatitis from pancreatic ductal adenocarcinoma

Morphology plays an important role in the distinction of autoimmune pancreatitis (AIP) from pancreatic ductal adenocarcinoma (PDAC). However, we aimed to determine the utility of immunohistochemical tumor markers to contribute in the distinction of these entities. In surgical specimens with AIP (n = 20), PDAC (n = 20) and normal pancreas (n = 20), the expression of pVHL, maspin, IMP3, S100P and Ki67 was examined. We evaluated intralobular reactive ducts / acinoductal metaplasia (ILDs) and extralobular ducts (ELDs) in AIP, neoplastic glands in PDAC, and ductal epithelium in the normal pancreas, using a five-tiered scoring system. The Ki67 hot spot index (Ki67-HSPI) was determined manually and using automated digital imaging analysis of virtual double stains of Ki67 and CK8. Besides, sequential dual-immunohistochemical staining of maspin/pVHL, maspin/IMP3 and Ki67/maspin was performed in a subset of the specimens. Strong overexpression of IMP3, maspin, S100P and Ki67 and loss of pVHL was observed in PDAC compared to AIP and normal pancreas. In AIP however, focal and weak aberrant expression was observed with the following proportions in ILDs/ELDs: pVHL in 45 %/85 %, maspin in 30 %/70 %, IMP3 in 55 %/5%, S100P in 10 %/35 % and Ki67-HSPI >20 % in 15 %/70 %. At least two markers were aberrantly expressed in ILDs/ELDs in 45 %/60 %. The aberrant expression was more pronounced in type 2 AIP compared to type 1. In conclusion, our data indicate that pVHL, maspin, IMP3, S100P and Ki67 can be focal and weak aberrantly expressed in AIP. However, when used as a panel, these markers seem to be useful for the differentiation of AIP from PC.     

Prognostic significance of maspin in pancreatic ductal adenocarcinoma: tissue microarray analysis of 223 surgically resected cases.

Maspin (SERPINB5), a serine proteinase inhibitor, was first identified as a potential tumor suppressor on the basis of its differential expression between normal mammary epithelial cells and human breast carcinoma cell lines. Recent studies have shown that maspin might be a prognostic tumor marker. Pancreatic ductal adenocarcinoma acquires maspin expression through hypomethylation of the maspin promoter. However, no study has investigated the prognostic significance of maspin expression in pancreatic ductal adenocarcinomas. In this study, we investigated maspin protein expression in a large series of 223 surgically resected pancreatic ductal adenocarcinomas using immunohistochemical staining and high throughput tissue microarrays. Maspin expression was correlated with postoperative survival and other clinicopathologic factors. Maspin was detected in 209 of these 223 (94% cases) pancreatic ductal adenocarcinomas including 39 (18% cases) focal (5-50% tumor cells) and 170 (76% cases) diffuse (>50% tumor cells). Fourteen (or 6% cases) pancreatic ductal adenocarcinomas did not show maspin expression by immunohistochemical staining (<5% tumor cells). Normal ductal epithelium is not labeled with maspin. Overexpression of maspin in pancreatic ductal adenocarcinoma is associated with worse postoperative survival especially in patients whose tumors exhibit diffuse expression of maspin. After adjusting other clinicopathologic factors, maspin expression remains to be an independent adverse prognosticator for postoperative survival. Maspin expression is not associated with patient age, gender, tumor size, tumor pathologic stage, lymph node status, and vascular invasion or perineural invasion. Nuclear labeling of maspin is associated with better tumor differentiation although this staining pattern is not associated with a better prognosis. In addition, maspin overexpression is also observed in 48% low-grade (grades 1a and 1b) pancreatic intraepithelial neoplasias (PanINs) and 78% high-grade (grades 2 and 3) PanINs, suggesting that maspin upregulation occurs early during the multi-step progression model of pancreatic ductal adenocarcinoma.     

Murine pancreatic ductal adenocarcinoma produced by in vitro transduction of polyoma middle T oncogene into the islets of Langerhans.

Pancreatic islets isolated from juvenile but not aging adult mice, when infected with a retrovirus carrying polyomavirus middle T oncogene, produced cell lines, mPAC, with characteristics both of pancreatic ductal epithelium and neuroendocrine cells of the islets. Following three cycles of single cell cloning, mPAC cells consisted of two subtypes, a null cell, and a double-positive cell that co-expressed cytokeratin, a marker of ductal epithelium, and A2B5, a neuroendocrine ganglioside expressed in developing islet cells. Two islet cell genes, encoding somatostatin and pancreatic polypeptide, were transcribed at low levels in most mPAC clones, whereas the insulin and glucagon genes were not. Upon inoculation of mice, mPAC cells rapidly formed well-differentiated ductal adenocarcinomas that expressed cytokeratin but not the islet cell markers. The mPAC phenotype may result from a specific dedifferentiation of juvenile islet cells or ductal epithelium induced by middle T protein. Alternatively, mPAC cells may arise by transformation of a multipotential progenitor present within or in juxtaposition to juvenile islets. This cell type could therefore represent one of the targets in human cancers of the pancreatic duct. Moreover, signal transduction systems modulated by middle T, including src-related kinases, phosphatidylinositol kinase, and protein phosphatase 2A, may be involved in pancreatic carcinogenesis.     

Histidine decarboxylase expression in pancreatic endocrine cells and related tumors

Histidine decarboxylase (HDC) is an enzyme for decarboxylating l-histidine to histamine and is expressed in various types of cells including neuroendocrine tumors. Recent findings have demonstrated a high percentage of HDC immunoreactivity in many neuroendocrine tumors, including carcinoid tumors, small cell carcinomas of the lung, pheochromocytomas, and medullary carcinomas of the thyroid. HDC immunostaining was applied to pancreatic islet cells and related tumors to explore possible expression of HDC as a wide spectrum marker for neuroendocrine differentiation. A total of 24 cases (22 pancreatic endocrine neoplasms, one small cell carcinoma of the pancreas, and one mixed exocrine-endocrine carcinoma) along with normal pancreatic tissue were immunostained with the anti-HDC antibody. In a normal pancreas, a double immunostaining revealed possible colocalization of HDC with glucagon- or insulin-positive cells in the islets. Seventeen of 22 pancreatic endocrine neoplasms (77%) were found to be positive for HDC, and no distinct relation to hormonal activity was observed. One small cell carcinoma was strongly positive to HDC. One non-functional tumor with mixed exocrine and endocrine components showed a diffuse positive immunostaining for HDC, and some neoplastic glucagon- or somatostatin (SRIF)-positive cells coexpressed HDC. In conclusion, we demonstrated that the majority of pancreatic endocrine tumors expressed HDC, and we suggest that HDC is a wider new marker for neuroendocrine differentiation.