福嶋 敬宜

Direct fast scarlet 4BS（以下，DFS）はアミロイド物質を特異的に染色するが，時としてアミロイドの染色不良や膠原線維への共染を経験する。これらの予防策として，塩を添加することによる染色液の調整法がこれまでいくつか報告されている。本検討では塩の種類・組み合わせに焦点を当て，DFS染色液調整法の検討を行った。DFS染色液に塩化ナトリウム，炭酸ナトリウム，硫酸ナトリウムの3種類の塩をそれぞれ添加した。さらに，これらの塩から任意の2種類を組み合わせて添加したもの，塩を添加しないコントロールを含む計7系列の染色液を作製した。全身性アミロイドーシス（AA型）と診断された剖検例の肝臓パラフィンブロックの連続切片を作製し，各系列のDFS染色液で染色した。染色した切片に対して，（1）アミロイドの染色性，（2）膠原線維への共染の程度を評価した。染色性の評価は，目視に加え，色の差を数値化す

Mucinous cystic neoplasms (MCNs) of the pancreas are primary pancreatic cyst-forming neoplasms that can be a precursor to invasive adenocarcinoma of the pancreas. MCNs occur almost exclusively in the distal pancreas of middle-aged women. MCNs typically show a "cyst-in-cyst" pattern of growth and are well encapsulated by a thick fibrous wall. MCNs are composed of mucin-producing neoplastic epithelial cells and "ovarian-type" subepithelial stroma. The epithelium is dysplastic and the grade can range from low to high grade; some MCNs have an associated invasive carcinoma. It is this associated invasive carcinoma that determines prognosis. MCNs harbor several characteristic genetic and epigenetic alterations, some of which are shared with conventional invasive pancreatic ductal adenocarcinoma. Furthermore, several studies reveal characteristic patterns of gene expression in the ovarian-type stroma that suggest steroidogenesis in the ovarian-type stroma. Better knowledge of the molecular alterations could help in the management of patients with this type of precursor of invasive carcinoma. (C) 2014 Elsevier Inc. All rights reserved.

A 54-year-old Japanese woman was referred with a gallbladder tumor. Based on the results of the computed tomography scan, endoscopic retrograde cholangiopancreatography, and magnetic resonance cholangiopancreatography, a mucin-producing neoplasm of the gallbladder associated with pancreaticobiliary maljunction was diagnosed. Extended cholecystectomy, extrahepatic bile duct resection, and choledochojejunostomy were performed, and she remains free of recurrence 24 months after resection. Histopathological examination revealed that the papillary component of the lesion was an intracystic papillary neoplasm with diverse characteristics of pancreaticobiliary epithelium and intestinal epithelium including mucin. In this component, most of the papillary lesion was a high-grade intraepithelial neoplasm, but also showed slight invasion into the muscular layer. The nodular component consisted of both poorly differentiated biliary type adenocarcinoma and large cell neuroendocrine carcinoma. We report a rare case of a mixed adenoneuroendocrine carcinoma arising from an intracystic papillary neoplasm associated with pancreaticobiliary maljunction. As for the histogenesis of this tumor, based on the histopathologic appearance, transdifferentiation from poorly differentiated biliary type adenocarcinoma to large cell neuroendocrine carcinoma is considered the most possible histogenesis of this tumor.

Adrenocortical oncocytomas are rarely reported, occur almost exclusively in adults, and are mostly nonfunctional. Here, we report an interleukin-6 (IL-6)-producing adrenocortical oncocytoma in an 11-year-old girl presenting with fever, body weight loss, and increased levels of inflammatory markers and serum IL-6. Imaging studies revealed a 4-cm mass in the left adrenal gland. After complete resection, laboratory findings returned to normal. Histology was consistent with adrenocortical oncocytoma, and the tumor cells stained positive for IL-6. Conclusion: IL-6-producing adrenocortical oncocytoma should be included in the differential diagnosis and imaging studies should be performed in patients presenting with persistent fever of unknown origin and high levels of inflammatory markers.

This report documents 3 pediatric papillary thyroid carcinoma cases with associated Hashimoto thyroiditis. In all 3 cases, hypoechoic nodules accompanied by multiple echogenic spots were noted on sonography of the thyroid. Hashimoto thyroiditis was suspected on the basis of positive thyroid autoantibody test results and pathologic examinations of thyroidectomy specimens, which revealed chronic thyroiditis with lymphocytic infiltration as the background of papillary thyroid carcinoma development. The potential for papillary carcinoma development warrants close follow-up, and meticulous sonographic examinations must be performed in children with Hashimoto thyroiditis.

The purpose of this study was to evaluate the clinical features, pathology, and etiology of adenocarcinoma in patients with anal fistulae.We identified seven patients diagnosed with adenocarcinoma associated with anal fistulae from a retrospective chart review.Five patients were diagnosed with primary adenocarcinoma associated with anal fistulae. Two patients were diagnosed with secondary adenocarcinoma associated with anal fistulae originating from rectal cancer on the proximal side. The primary adenocarcinomas included cancers arising from long-standing anal fistulae fulfilling established diagnostic criteria in two patients, and cancer arising from short-duration anal fistulae in three patients. Excision of the fistula was performed based on the initial diagnosis of the anal fistula for all five patients. Increased suspicion of cancer was due to the existence of gelatinous material in the anal fistula in three patients and induration in the resected specimens in two patients. The etiologies of the secondary adenocarcinomas associated with anal fistulae included implantation in the anal fistula from rectal cancer and fistula formation originating due to the progression of rectal cancer.Anal fistulae are commonly seen in the coloproctology clinic, but special attention to similar conditions associated with malignant disease is needed.

Objective We retrospectively investigated the clinical features of pulmonary aspergillosis associated with interstitial pneumonia. Methods We reviewed the medical records of all patients treated for interstitial pneumonia with or without pulmonary aspergillosis at our institution between April 2006 and August 2012 and evaluated the clinical features as well as risk and prognostic factors for pulmonary aspergillosis associated with interstitial pneumonia. Results Among 539 patients with interstitial pneumonia, 15 who suffered from pulmonary aspergillosis were identified. The median age was 69.2 +/- 7.0 years, and fourteen patients were men. The subtypes of pulmonary aspergillosis were chronic pulmonary aspergillosis (n=14) and invasive pulmonary aspergillosis (n=1). The forms of interstitial pneumonia included idiopathic pulmonary fibrosis (n=9), rheumatoid arthritisrelated interstitial pneumonia (n=4) and pleuroparenchymal fibroelastosis (n=2). The underlying conditions were emphysema (n=9) and a history of oral corticosteroid and/or immunosuppressive use (n=4). Home oxygen therapy (HOT) was administered in 11 patients. Following the diagnosis of pulmonary aspergillosis, all patients were treated with antifungal drugs. Ten patients (66.6%) died. A comparison of the interstitial pneumonia patients with and without pulmonary aspergillosis showed that the presence of emphysema, use of HOT and death were significantly associated with pulmonary aspergillosis. Conclusion Pulmonary aspergillosis is one of the major complications of interstitial pneumonia and its prognosis is poor. Therefore, providing careful monitoring and proper treatment is extremely important.

Numerous reports have demonstrated the usefulness of bioresorbable materials, but few have described severe complications caused by delayed degradation. The authors present the case of an intracranial foreign body granuloma caused by plates made of unsintered hydroxyapatite (uHA) particles and poly-L-lactide (PLLA; Super Fixsorb MX, Takiron) after cranioplasty. This 1-month-old boy presented to the authors' department with Pfeiffer syndrome. He had multiple-suture synostosis causing turribrachycephaly, Chiari malformation Type 1, and obstructive sleep apnea syndrome. At 6 months old, the child was treated with multidirectional cranial distraction osteogenesis. The uHA-PLLA plates were applied as base stones to reinforce the pins. After 16 days of distraction and 3 weeks of consolidation, the pins were removed. Seventeen months postoperatively, the plate on the right temporal bone showed passive intraosseous translocation (PIT), and by 2 years postoperatively, the plate was completely left behind in the cerebrum. At 3.5 years postoperatively, MRI disclosed a contrast-enhanced mass with surrounding brain edema at the site of the plate. The lesion was resected. The clinical history and histological specimens led to a diagnosis of foreign body granuloma surrounding the nonabsorbed resorbable plate in the dura mater. Resorbable plates are clearly useful resources in cases in which delayed absorption will not prove problematic, but careful application and follow-up is required when dealing with the growing skull given the possibility of intracranial displacement after PIT.

A solid pseudopapillary neoplasm (SPN) of the pancreas has distinct histopathological features. A solid pattern of growth with pseudopapillary structures that result from degeneration is observed. On rare occasions, the tumor may vary from being entirely solid to completely cystic. The present study describes two unique cases of SPN. A 25-year-old male presented with a pancreatic tumor showing a predominantly solid pattern with no degenerative change, although the pre-operative cytological specimens that were obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) revealed pseudopapillary structures. The second case was of an 11-year-old female who presented with a pancreatic tumor with prominent degeneration. Nests and cords of the remaining neoplastic cells were located only at the periphery, with perineural invasion. An immunohistochemical analysis revealed that the tumor cells in the two cases were positive for CD10 and beta-catenin and negative for trypsin. An awareness of the broad morphological variability of SPN and an immunohistochemical panel that includes CD10, beta-catenin and trypsin are useful for establishing an accurate diagnosis.

Lynch syndrome, also referred to as hereditary nonpolyposis colorectal cancer, is the most common form of hereditary colorectal cancer, and is associated with a high incidence of multiple primary neoplasms in various organs.A 79-year-old woman (patient 1) diagnosed with ascending colon cancer had a history of previous carcinomas of the uterus, stomach, uroepithelial tract, and colon. One year later, she developed a brain tumor (glioblastoma). A 54-year-old female (patient 2) was diagnosed with endometrial cancer and sigmoid colon cancer. Both patients underwent genetic evaluations independently.No mutations were found in an exon-by-exon analysis of genomic DNA by polymerase chain reaction (PCR) and reverse transcription (RT)-PCR. However, multiplex ligation-dependent probe amplification (MLPA) identified genomic duplication spanning from exon 7 to exon 14 of the MSH2 gene in both patients. Due to the presence of this characteristic gene duplication, their pedigrees were investigated further, and these showed that they are paternal half-sisters, consistent with paternal inheritance.Large genomic duplication from intron 6 through intron 14 in MSH2 is a very rare cause of Lynch syndrome and is difficult to identify with conventional methods. MLPA may be an alternative approach for detecting large-scale genomic rearrangements.

Recurrent respiratory papillomatosis (RRP), a chronic upper respiratory condition characterized by diffuse multiple recurring papillomas, is thought to result from human papillomavirus (HPV) type 6 or 11 infection. Although RRP is an intractable disease, malignant transformation of RRP is rare. The underlying mechanism, however, has not been elucidated. We describe the clinical course of a patient who underwent more than 130 operations for RRP associated with HPV type 6 infection and subsequently suffered spontaneous malignant transformation to squamous cell carcinoma. Immunohistochemical analysis revealed that malignant transformation might result from a genomic defect, such as p53 inactivation, leading to stimulation of uncontrolled cell proliferation by HPV type 6 for an extended period, but not directly because of HPV itself. Our results could help in the development of novel therapeutic strategies for severe RRP, although further studies are required before clinical application of molecular targeted therapies. © 2013 Kanazawa et al.

The 6th Diagnostic Pathology Summer Fest, held in Tokyo on August 25-26, 2012, opened its gates for everyone in the medical profession. Basic pathology training can contribute to the improvement of algorithms for diagnosis and treatment. The 6th Summer Fest with the theme 'Pathology and Clinical Treatment of Gastrointestinal Diseases' was held at the Ito International Research Center, The University of Tokyo. On August 25, Treatment of Early Gastrointestinal Cancer and New Guidelines' was discussed in the first session, followed by 'Biopsy Diagnosis of Digestive Tract: Key Points of Pathological Diagnosis for Inflammation and Their Clinical Significance' in the second session. On August 26, cases were discussed in the third session, and issues on pathological diagnosis and classification of neuroendorcrine tumor in the fourth session. The summaries of speeches and discussions are introduced along with the statements of each speaker. This meeting was not a formal evidence-based consensus conference, and 20 experts gave talks on their areas of specialty. Discussion was focused on how the management strategy should be standardized on the algorithm of patient care. (C) 2013 S. Karger AG, Basel

Intestinal strangulation caused by a mucocele of the appendix is extremely rare and difficult to diagnose. It is not usually suspected pre-operatively. This report presents a case of intestinal strangulation due to a mucous containing cystic lesion that was wrapped around the base of a loop of the small bowel. An 89-year-old female was transferred after an acute onset of abdominal pain. A physical examination revealed severe tenderness with guarding in the right upper quadrant. CT of the abdomen showed a loop of dilated small bowel with edema on the right side of the abdominal cavity suggesting a closed loop obstruction. In addition, a low-density thin-walled mass measuring 5 cm in diameter was also seen in the pelvis. Intestinal strangulation was suspected and emergency laparotomy was thus performed. A loop of terminal ileum 25 cm in length was strangulated by a dilated appendix, and ileocecal resection was performed. The resected appendix measured 9 x 3 cm in size and contained mucus. A histopathological examination showed a mucous containing cystic appendix without mucin-producing, neoplastic epithelial cells. A mucocele of the appendix can present in various ways and it is important to recognize this entity at the time of surgery.

We describe a case of an adult female who presented with nephrotic syndrome. She was diagnosed with systemic lupus erythematosus with serum antinuclear antibodies, leucopenia with lymphopenia, butterfly erythema, and nephrotic syndrome. Renal biopsy revealed normal glomeruli with diffuse effacement of the foot processes, consistent with lupus podocytopathy. Although human albumin replacement was performed initially, acute renal failure developed rapidly. Therefore, she was treated with double filtration plasmapheresis (DFPP) in addition to oral steroid. After steroid therapy combined with DFPP, the renal function and proteinuria improved rapidly. Although the impact of DFPP on the treatment of lupus nephritis remains to be delineated, our observations suggest that DFPP in lupus podocytopathy played a pivotal role in facilitating the early recovery from renal injuries. Because of the rapid improvement of renal function without any change in body weight by DFPP, acute renal failure in the setting of lupus podocytopathy might contribute to an alternative pathophysiological factor for the diminished glomerular filtration rate, similar to that observed in the setting of idiopathic minimal change glomerulopathy.

Purpose To retrospectively evaluate criteria for differentiating biliary tract changes in autoimmune pancreatitis (AIP-BTC) from extrahepatic cholangiocarcinoma (ECCA) based on CT findings and to determine predictors for differentiation between the two disorders. Materials and methods CT findings of 22 patients with AIP-BTC and 45 patients with ECCA, both with positive CT findings in the biliary system, were retrospectively assessed. The images were assessed for presence of biliary obstruction, diameter of the maximally dilated biliary duct, maximum thickness of the involved duct, presence of masses inside or around the involved ducts, lengths of the biliary lesions, concentricity of wall thickening, multifocality of the lesion, and degree of lesion enhancement. Results Compared with AIP-BTC, ECCA was significantly more frequently associated with biliary obstruction (p = 0.0037), shorter lengths of the biliary lesions (p = 0.0036), and masses (p < 0.001). No significant differences were found for other items. Conclusion Presence of obstructive dilatation of the bile ducts and intraluminal or peri-ductal masses and length of the thickened wall may help differentiate between AIP-BTC and ECCA.

Objectives: There have been only a few reports on follow-up results of serous cystic neoplasm (SCN) of the pancreas. The frequency of malignancy and surgical indication of SCN are not determined yet. Methods: In this multi-institutional study of the Japan Pancreas Society, a total of 172 patients with SCN were enrolled. The mean follow-up period was 4.5 years. Surgical resection was performed in 90 patients, whereas the remaining 82 were simply observed. Results: Of all patients, 20% were symptomatic. The tumor was located in the pancreatic head (39%), body (35%), and tail (22%). The mean diameter of the tumor was 4.1 cm. None of the patients showed distant or lymph node metastasis except for liver metastasis found in 2 patients (1.2%). No patient died during the follow-up. The preoperative diagnosis did not correctly identify SCN in 57 (63%) of 90 resected cases. A honeycomb appearance, which is one of the most characteristic findings of SCN, could be diagnosed better by endoscopic ultrasonography than by other imaging diagnostic modalities. Conclusions: Surgical resection should be considered only when clear distinction from other surgical diseases is difficult, when symptoms or mass effects are present, and when the tumor size is large.

Glomerular crescents are most commonly associated with rapidly progressive crescentic glomerulonephritis; however, they also develop in response to a wide range of primary and secondary glomerular injuries. Since various kind of glomerulopathies occasionally overlay diabetic glomerular injuries, the presence of crescents in renal biopsy specimens of diabetics may have stimulated a search for etiologies other than diabetes. In this report, we describe an unusual case of diabetic glomerulosclerosis with peculiar extracapillary proliferation. Although such a relationship has so far been ignored in most of the literature, the etiological linkage between diabetic glomerulosclerosis and the development of crescents may not be exceptional. We have reviewed the previous literature and herein discuss the pathological implications of the development of crescents in patients with diabetic glomerulosclerosis. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3950457896920255.

Intraductal papillary mucinous neoplasm (IPMN) is recognized as a precursor lesion to pancreatic cancer, a unique pathological entity. IPMN has subtypes with different clinical characteristics. However, the molecular mechanisms of cancer progression from IPMN remain largely unknown. In this study we examined the differences in genetic alteration(s) among the IPMN subtypes. Surgically resected IPMNs (n = 25) were classified into four subtypes by hematoxylin and eosin (H&E) and mucin immunostaining. Mutations in KRAS, BRAF, and PIK3CA genes and expression of CDKN2A, TP53, SMAD4, phospho-ERK, and phospho-SMAD1/5/8 proteins were examined. There were 11 gastric, 11 intestinal, one pancreatobiliary, and two oncocytic types in this study. We then compared the two major subtypes, gastric-type and intestinal-type IPMN. Gastric-type IPMN showed a significantly higher incidence of KRAS mutations (9/11, 81.8%) compared with intestinal type (3/11, 27.3%; p < 0.05), although the intestinal type showed a higher grade of dysplasia than gastric type (p < 0.01). All cases with KRAS mutations showed phospho-ERK immunostaining. In contrast, intestinal type (9/11, 81.8%) showed more frequent SMAD1/5/8 phosphorylation compared with gastric-type IPMN (3/11, 27.3%; p < 0.05%). There may be distinct mechanisms of pancreatic cancer progression in the different subtypes of IPMN. In particular, KRAS mutation and bone morphogenetic protein-SMAD signaling status may be crucial diverging steps for the two representative pathways to pancreatic cancer in IPMN patients.

Langerhans cell histiocytosis (LCH) is a clonal neoplasm that shows diverse clinical manifestations and courses of disease progression. The etiology and pathophysiology of LCH remain uncertain. We describe the clinical course of a 23-year-old Japanese woman with multi-system LCH, who showed rapid progression after steroid reduction and developed multi-organ failure. Liver biopsy showed LCH infiltration with fatty degeneration. She was treated with cytarabine, vincristine, and prednisolone according to the Japan LCH study group 02 protocol, without any clinical improvement. Low expression of Ki67 and bcl-2 failed to explain the rapid clinical course. Panhypopituitarism and hypothalamic dysfunction may have caused nonalcoholic fatty liver disease and liver failure. This case indicates that some multi-system LCH patients with hypopituitarism and hypothalamic dysfunction show very rapid progression and are difficult to treat. [J Clin Exp Hematopathol 52(2) : 121-126, 2012]

Forty-eight patients with gastrointestinal (GI) tract B-cell lymphoma (BCL) were analyzed retrospectively. The diagnosis was based on the histological examination of specimens obtained by endoscopic biopsy. Before the diagnosis was made, single-color flow cytometry was performed to analyze the expression of light chains and B-cell antigens including CD10 in the specimens. Restricted light chain (RLC) expression, a marker of B-cell clonality, was defined as κ and λ ratios of either more than 3.0 or less than 0.5. The specimens from 30 patients (62.5%) showed RLC expression. No RLC expression or RLC expression not examined was divided into two groups : those showing CD10 positivity in more than 20% of cells (4 patients, 8.3%) and those showing no positivity (14 patients, 29.2%). The cell number analyzed in the latter group was significantly smaller than that in the other two groups. Abnormal karyotypes were found in the specimens from 8 patients (16.7%). These results indicate that the flow cytometric analysis of endoscopic biopsy specimens is useful when BCL is suspected if an adequate number of cells are obtained. [J Clin Exp Hematopathol 52(2) : 127-131, 2012]

Introduction. Primary involvement of the salivary glands in small cell carcinoma is rare, and has one of the worst prognoses of salivary gland neoplasms. However, it has been reported that some cases have a favorable outcome, although the prognostic factors are still under consideration. Multidisciplinary therapy was usually required to achieve long-term survival. Recently, a resemblance of some small cell carcinomas of the salivary gland to cutaneous Merkel cell carcinoma was suggested the latter have the potential for spontaneous regression, which is related to a favorable clinical outcome. Case presentation. We present a locoregional advanced parotid small cell carcinoma with multiple lymph node metastases in an 87-year-old Asian woman. The tumor was controlled by surgery alone, and nine-year disease-free survival was achieved without any adjunctive therapy. To the best of our knowledge, this is the longest reported follow-up of head and neck small cell carcinoma. Conclusion: We believe this to be the first case of small cell carcinoma with involvement of the salivary glands reported in the literature with a good outcome after surgery alone without any adjunctive therapy. © 2012 Kanazawa et al. licensee BioMed Central Ltd.

Pancreatic ductal neoplasms exhibit gastric epithelium-like characteristics. In this study, we evaluated the expression of claudin-18 (CLDN18), a gastric epithelium-associated claudin, in pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and pancreatic ductal adenocarcinomas (PDACs) using immunohistochemistry. We observed a high level of expression of CLDN18 in PanINs (31/32, 97%), IPMNs (61/65, 95%), and MCNs (4/5, 80%) using ordinary tissue section analysis. Furthermore, we observed a high level of CLDN18 expression in PDACs (109/156, 70%) using tissue microarray analysis. However, the normal pancreatic duct or the ductal metaplasia of the acinar cells was not immunoreactive. Comparative analysis of CLDN18 and phenotypic markers in IPMNs revealed that simultaneous expression of CLDN18 and intestinal markers frequently occurred, even in intestinal-type IPMNs. CLDN18 variant 2 mRNA was expressed and was similarly upregulated by phorbol 12-myristate 13-acetate (PMA) treatment in pancreatic cancer cell lines and in a gastric cancer cell line. An inhibitor of pan-PKC (GF109203X) completely suppressed this upregulation in pancreatic cancer cells. These results indicate that CLDN18, a marker for the early carcinogenetic process, is commonly expressed in precursor lesions of PDAC. Activation of the PKC pathway might be involved in CLDN18 expression associated with pancreatic carcinogenesis. (J Histochem Cytochem 59:942-952, 2011)

Objective: The aim of this study was to elucidate the clinicopathological features and prognosis of mucinous cystic neoplasms (MCNs).Materials and Methods: We performed a multi-institutional, retrospective study on a collected series of patients with MCN pathologically defined by ovarian-type stroma. Clinicopathological features and prognosis were investigated.Result: Mucinous cystic neoplasm was confirmed in 156 cases, including 129 adenomas (82.7%) and 21 noninvasive (13.4%) and 6 invasive carcinomas (3.9%). Patients with MCN were exclusively women (98.1%) with the mean age of 48.1 years. All but 1 MCN were in the pancreatic body/tail region with a mean size of 65.3 mm. Communication between the cyst and the pancreatic duct was found in 18.1%. The 3-, 5-, and 10-year survival rates were 97.6%, 96.6%, and 96.6%, respectively. A significant difference in the survival rates was observed between adenomas and carcinomas and between minimally invasive carcinomas and invasive carcinomas. Cyst diameter and presence of mural nodule were predictive of malignant MCN.Conclusions: Mucinous cystic neoplasm is a rare but distinctive pancreatic cystic neoplasm with a favorable overall prognosis. All MCNs should be resected to prevent malignant changes but can be observed an appropriate time when the lesion is small without the presence of mural nodules.

Most patients with thymic cysts complain of a slowly enlarging, asymptomatic cervical mass. Only 6-10% suffer dysphagia, dyspnoea, stridor, cervical pain or vocal paralysis. In some rare cases sudden onset of severe dyspnoea or asphyxia is the first symptom, especially in neonates and small infants. We report a unique case of a 20-month-old child, who required emergency tracheal intubation due to asphyxia. Cervicomediastinal thymic cyst might need to be included in causes of life-threatening airway obstruction in young children.

Intraductal oncocytic papillary neoplasm is known as a distinct subtype of intraductal papillary mucinous neoplaSm of the pancreas. Similar neoplasms of the bile duct are rarely reported, and their disease characteristics are not well established. In this study, we examined 6 cases of biliary neoplasms consisting of oncocytic cells with almost exclusively intraductal growth. The patients were 5 women and I mail of 51 to 68 years. Grossly, 4 appeared to be cystic neoplasms with papillary projections located in the liver and the other two were papillary neoplasms of the dilated hilar bile duct that ranged from 1.5 to 16 cm in size. The most prominent neoplastic cells were cuboidal epithelial cells that showed abundant eosinophilic granular cytoplasm with strongly positive staining for antimitochondrial antibody. Four neoplasms were mixed with minor components of nononcocytic cells. All neoplasms showed arborized papillary and/or cribriform formations except one, which showed a villous architecture. All neoplasms were adenocarcinomas accompanied by a microscopic minimally invasive carcinoma. The oncocytic neoplastic cells, as well as the nononcocytic cells, produced gastric-type mucin (MUC5AC and MUC6) and showed claudin18 and HepPar-1 positivity. Five patients lived disease-free for 10 to 112 months after resection, and I died of tumor recurrence at 26 months postoperatively. The present series of biliary tumors are intraductal papillary neoplasms with oncocytic features and call be clinicopathologically regarded as counterparts of pancreatic intraductal oncocytic papillary neoplasm. Our results also Suggest that oncocytic changes occur in epithelial cells of biliary tracts that show a predominant gastric phenotype. (C) 2009 Elsevier Inc. All rights reserved.

Background and aims Infiltration of IgG4-positive plasma cells in the pancreas and other organs is characteristic of autoimmune pancreatitis (AIP). However, it is undetermined whether needle or forceps biopsy of pancreas or other organs is indeed useful for the diagnosis of AIP. We aimed to clarify this point. Methods Among 39 AIP patients, tissue sampling without laparotomy was performed in 27. Biopsy of pancreas, gastric mucosa, liver, bile duct, and duodenal papilla was performed in 15, 17, 11, 5 and 7, respectively. The obtained specimens were examined for IgG4-positive plasma cells. We also examined gastric mucosa of 18 patients with pancreatic cancer as controls. When the number of IgG4-positive plasma cells was more than 10 per high-power field, we regarded it as diagnostic. Results Diagnostic sensitivity in pancreas, gastric mucosa, liver, bile duct, and duodenal papilla was 47% (7/15), 47% (8/17), 36% (4/11), 0% (0/5), and 57% (4/7), respectively. Conclusions Sensitivity of IgG4 immunostaining was unsatisfactory when tissue sampling was performed by needle or forceps biopsy. Biopsy of gastric mucosa might be a good subsidiary diagnostic tool.

BACKGROUND: We have often encountered difficulties in identifying small liver cancers during surgery. Fluorescent imaging using indocyanine green (ICG) has the potential to detect liver cancers through the visualization of the disordered biliary excretion of ICG in cancer tissues and noncancerous liver tissues compressed by the tumor. METHODS: ICG had been intravenously injected for a routine liver function test in 37 patients with hepatocellular carcinoma (HCC) and 12 patients with metastasis of colorectal carcinoma (CRC) before liver resection. Surgical specimens were investigated using a near-infrared light camera system. Among the 49 subjects, the 26 patients examined during the latter period of the study (20 with HCC and 6 with metastasis) underwent ICG-fluorescent imaging of the liver surfaces before resection. RESULTS: ICG-fluorescent imaging identified all of the microscopically confirmed HCCs (n=63) and CRC metastases (n=28) in surgical specimens. Among the 63 HCCs, 8 tumors (13%, including 5 early HCCs) were not evident grossly unless observed by ICG-fluorescent imaging. Five false-positive nodules (4 large regenerative nodules and 1 bile duct proliferation) were identified among the fluorescent lesions. Well-differentiated HCCs appeared as uniformly fluorescing lesions with higher lesion-to-liver contrast than that of moderately or poorly differentiated HCCs (162.6 [71.1-218.2] per pixel vs 67.7 [-6.3-211.2] per pixel, P<.001), while CRC metastases were delineated as rim-fluorescing lesions. Fluorescent microscopy confirmed that fluorescence originated in the cytoplasm and pseudoglands of HCC cells and in the noncancerous liver parenchyma surrounding metastases. ICG-fluorescent imaging before resection identified 21 of the 41 HCCs (51%) and all of the 16 metastases that were examined. CONCLUSIONS: ICG-fluorescent imaging enables the highly sensitive identification of small and grossly unidentifiable liver cancers in real time, enhancing the accuracy of liver resection and operative staging. Cancer 2009;115:2491-504. (C) 2009 American Cancer Society.

Desmoplasia is a common feature of infiltrating ductal adenocarcinoma of the pancreas. This process is intricately interacted between the host and neoplastic cells. Recently, by transcriptome analysis, periostin was identified as a significantly highly expressed gene in pancreatic stellate cells. To investigate the characteristics of periostin immunodeposition in pancreatic ductal neoplasms, we performed immunohistochemistry and in situ hybridization, focusing on tumor -stromal cells interactions. Eighty-one surgically resected pancreatic lesions, including 35 pancreatic ductal adenocarcinoma, 26 intraductal papillary-mucinous neoplasms, 11 mucinous cystic neoplasms and 9 chronic pancreatitis, were studied. In all ductal adenocarcinomas, periostin deposition was observed in the stroma around the infiltrating cancer on immunohistochemistry. Cellular stroma of mucinous cystic neoplasm, called 'ovarian-type' stroma, did not show periostin deposition. In chronic pancreatitis, most of the staining patterns of periostin were perilobular and meshwork-like. Periostin gene expression was detected solely in the stromal cells on in situ hybridization. Intraductal papillary-mucinous neoplasms were classified into four groups on the basis of the histological grade, namely, adenoma, non-invasive adenocarcinoma, adenocarcinoma with microscopical invasion and with macroscopically evident invasion. In intraductal papillary-mucinous neoplasm, periostin deposition in the periductal stroma increased in frequency and intensity in adenocarcinoma compared with adenomas (P = 0.014). Furthermore, our results showed that a higher frequency of periostin deposition was correlated with a higher frequency of ` intestinal phenotype' of proliferating epithelium (P = 0.036) and laminin-5 gamma 2 chain expression (P<0.001) in intraductal papillary-mucinous neoplasm, the latter of which is frequently expressed in invasive carcinoma. This is the first report to describe the periostin immunohistochemistry in intraductal papillary mucinous neoplasm of the pancreas.

Reported herein is a case of endometrial adenocarcinoma without myometrial invasion that metastasized to the pancreas in a 69-year-old Japanese woman who had a history of hysterectomy. Although systemic radiography could not detect any metastasis in the whole body before hysterectomy, imaging performed 2 months after the hysterectomy consisting of CT, magnetic resonance imaging, gallium scintigraphy and positron emission tomography identified a solitary pancreatic tumor. Imaging demonstrated an intracystic papillary growth in the pancreas, suggesting intraductal papillary mucinous neoplasm or mucinous cystic neoplasm. Excised in distal pancreatectomy, the tumor was diagnosed as a pancreatic primary, an invasive papillary adenocarcinoma at first, but both the endometrial tumor and the pancreatic tumor demonstrated similar morphology and immunohistochemistry. Furthermore, the identical nucleotide mutation of TP53 gene was observed from both the endometrial and pancreatic tumors. The pancreatic tumor was therefore confirmed to be a metastasis from the primary endometrial adenocarcinoma. Metastasis to the pancreas from endometrial carcinoma is extremely rare but must be considered even if the previous cancer was treated at an early stage. Histopathological comparison study and genetic analysis are important for the correct diagnosis of metastasis.

In contrast to the relatively uniform pathology and the unyielding dismal outcome associated with infiltrating ductal adenocarcinoma of the pancreas, cystic lesions have a broad spectrum of gross and microscopic pathologies, and a range of clinical outcomes. The common cystic lesions of the pancreas are reviewed with emphasis on practical tips for distinguishing between the main entities. © 2008 Elsevier Ltd. All rights reserved.

KRAS2 gene mutations are found in 75-90% of infiltrating pancreatic ductal adenocarcinomas but can also be present with other nonneoplastic pancreatic diseases. We recently developed a novel sensitive assay for point mutation detection, called "LigAmp", which can detect one mutant molecule in the presence of 10,000 wild-type molecules and can quantify mutant DNA over a wide dynamic range. We analyzed KRAS2 mutations in surgically-collected pancreatic duct juice samples from patients with pancreatic adenocarcinoma ( n = 27) and chronic pancreatitis ( n = 9). DNA sequencing demonstrated that 17 of the 27 pancreatic cancers harbored KRAS2 mutations at codon 12, including G12D ( GGT -> GAT), G12V ( GTT), and G12R ( CGT). We determined the relative amounts of each KRAS2 mutant by simultaneously quantifying wild-type and mutant KRAS2 DNA. For all pancreatic adenocarcinoma patients, the dominant KRAS2 mutation detected in the pancreatic juice corresponded to that found in the primary cancer. Mutation levels were substantially higher in patients with pancreatic cancer ( 0.05 to 82% of total KRAS2 molecules) compared to those with chronic pancreatitis ( 0 to 0.7%). Among patients with mutant KRAS2 positive cancers, all but one ( 94%) had mutant KRAS2 DNA concentrations of more than 0.5% in their pancreatic juice samples, whereas only 1 of 9 ( 11%) pancreatic juice samples from patients with chronic pancreatitis had more than 0.5% mutant KRAS2 DNA, corresponding to a sensitivity of 94% and a specificity of 89%. LigAmp quantification of mutant KRAS2 in pancreatic juice differentiates pancreatic adenocarcinoma from chronic pancreatitis, and may be a useful early detection tool for pancreatic cancer.

Infiltrating adenocarcinoma of the pancreas is thought to develop through well-defined precursor lesions called pancreatic intraductal neoplasia (PanIN). Despite the exponential growth in our understanding of genetic events that characterize the progression of PanINs to invasive carcinoma, little is known about the role of epigenetic alterations in these precursor lesions. To define the timing and prevalence of methylation abnormalities during early pancreatic carcinogenesis, we investigated the CpG island methylation profile in the various grades of PanINs. Using methylation-specific PCR, we analyzed DNA samples from 65 PanIN lesions for methylation status of eight genes recently identified by microarray approach as aberrantly hypermethylated in invasive pancreatic cancer. Aberrant methylation at any of the eight genes was identified in 68% of all the PanIN lesions examined, and, notably, aberrant methylation was identified in more than 70% of the earliest lesions (PanIN-1A). The average number of methylated loci was 1.1 in PanIN-1A, 0.8 in PanIN-1B, 1.1 in PanIN-2, and 2.9 in PanIN-3 lesions (P = 0.01 for PanIN -3 vs earlier PanINs). Among the genes analyzed, NPTX2 demonstrated an increase in methylation prevalence from PanIN-1 to PanIN-2 (P = 0.0008), and from PanIN-2 to PanIN-3 for SARP2 (P = 0.001), Reprimo (P = 0.01), and LHX1 (P = 0.03). These results suggest that aberrant CpG island hypermethylation begins in early stages of PanINs, and its prevalence progressively increases during neoplastic progression.

Purpose: Most familial cancer susceptibility genes are tumor suppressor genes that are biallelically inactivated in familial neoplasms through somatic deletion of the wild-type allele. Identifying the genomic losses that occur in pancreatic neoplasms, particularly those that occur in familial and precursor neoplasms, may help localize the genes responsible for pancreatic cancer susceptibility. Experimental Design: Normal and neoplastic tissue DNA was isolated from fresh-frozen surgically resected tissues from 20 patients with primary familial pancreatic adenocarcinoma (defined as having at least one first-degree relative with pancreatic cancer), 31 with sporadic intraductal papillary mucinous neoplasms (IPMN), and 7 with familial IPMNs using laser capture microdissection. Microdissected DNA was whole genome amplified using multiple strand displacement. Genome-wide allelotypes were determined using 391 microsatellite markers. The accuracy of microdissection and fidelity of the whole genome amplification were determined by comparing the genotypes of microdissected primary pancreatic cancers to the genotypes of xenografts derived from these cancers and by comparing the results of amplified to nonamplified specimens. Results: The concordance of genotypes between LCM whole genome amplified primary pancreatic cancers and their corresponding pancreatic cancer xenograft DNAs was 98%. Among the 20 primary familial pancreatic adenocarcinomas, we found a high prevalence of loss of heterozygosity (LOH) with an average fractional allelic loss (FAL) of 49.9% of an aggregate of 2,378 informative markers. The level of FAL in the IPMNs (10%) was significantly lower than in the pancreatic adenocarcinomas. The most common locus of LOH in the IPMNs was at 19p (LOH at 24% of markers). The regions of frequent allelic loss observed in the familial pancreatic cancers were similar to those found in sporadic pancreatic cancers. Conclusions: The allelic loss patterns of familial and sporadic pancreatic cancers and IPMNs provide clues as to the genomic locations of tumor suppressor genes inactivated in these neoplasms.

Mucinous cystic neoplasm (MCN) of the pancreas is a distinct clinicopathological entity characterized by mucin-producing epithelial and cyst-forming neoplasm with "ovarian-type" stroma beneath the epithelial component. It is clearly distinguished from ductal adenocarcinoma and intraductal papillary mucinous neoplasm (IPMN). However, MCN can progress to infiltrating carcinoma, and frequently shows a similar histological pattern to ductal adenocarcinoma. Several genetic alterations such as K-ras oncogene mutation, and epigenetic alterations such as hypermethylation of p16 in the invasive component of MCN are also common with ductal adenocarcinoma. Furthermore, recent technologies, including a laser-assisted microdissection system for histological slides and global gene expression profilings using DNA microarrays, made possible to identify more information about molecular abnormalities of MCNs. It is important to diagnose the lesions before they progress to an invasive carcinoma. MCN is one of the precursors of invasive pancreatic carcinoma.

Background. Gemcitabine is an efficacious cytotoxic agent used in the treatment of unresectable pancreatic carcinoma (PC). Recently, gemcitabine resistance has been associated with the ribonucleotide reductase subunit M2 (RRM2). In this prospective study, we hypothesized that RRM2 expression in PC biopsy specimens would be a significant predictor of outcome. Methods. RRM2 mRNA expression in 35 endoscopic ultrasonography-guided fine needle aspiration biopsy (EUS-FNAB) samples was quantified using real-time quantitative reverse transcription -polymerase chain reaction. Results. Thirty-one of 35 biopsy specimens could be assessed for RRM2 expression levels. The mean RRM2 expression relative to glyceraldehyde-3-phcsphate dehydrogenase was 0.248 (range, 0.00739 to 0.858). Eighteen patients (64.5%) had low RRM2 levels, and 13 patients (35.5%) had high RRM2 levels with a cutoff of 0.1. The median survival was 8.8 months for patients with low RRM2 levels and 5.0 months for patients with high levels (P < 0.05). In the low RRM2 expression group, a complete response (CR) was observed in one patient, and a partial response (PR) was observed in eight patients. In contrast, in the high RRM2 expression group, PR was observed in one patient, and CR was not observed. The overall response rate between the high and low expression groups was significantly different (50.0% vs. 7.7%, P < 0.05). Conclusions. RRM2 mRNA expression of EUS-FNAB specimens is a key predictive marker of survival in gemcitabine-treated patients with PC.

Objectives: Histological subclassification of intraductal papillary mucinous neoplasms (IPMNs) is important because the malignant potential of each subtype is different. We investigated whether pancreatic juice cytology can be used to define the subtypes of IPMNs preoperatively. Methods: The cytological findings and pathological parameters in 19 cases of IPMN were analyzed for correlations. Pancreatic juice cytology specimens were reviewed and classified into 4 types according to the criteria previously described for histological diagnosis: intestinal (Int), gastric foveolar (GF), oncocytic (Onc), and pancreatobiliary (PB), and the resected IPMNs were classified histologically using the same criteria for comparison. Immunochemical testing for MUC proteins was also performed. Results: fit 15 cases (79%), the cytological and histological subclassifications were in agreement. The cytology specimens displayed different features corresponded to their histological subtypes. The sensitivities of the cytological diagnosis of each subtype were 80.0% (Int), 72.7% (GF), and 100% (Onc/PB); and the specificities were 85.7% (Int), 87.5% (GF), and 93.8% (Onc/PB). The cytoplasm of the Int-type cells in the pancreatic juice cytology specimens was positive for MUC2. Conclusions: Most of the cytological findings of IPMNs corresponded to the histological findings. The use of MUC2 immunocytochemistry in IPMN subtyping was also demonstrated. Subtyping of IPMNs is useful for preoperative evaluation in addition to cytomorphological grading.

Pancreatic cancer is the fourth leading cause of cancer death in the US. Most pancreatic cancers are infiltrating ductal adenocarcinomas. The careful application of well-defined morphologic criteria can be used to differentiate between infiltrating ductal adenocarcinoma and reactive glands. While most pancreatic cancers are ductal adenocarcinomas, a number of histologically defined variants have been described. These are important to recognize because they have distinct clinical pathologic features. Pancreatic intraepithelial neoplasia (PanIN) is the presumed precursor lesion to infiltrating ductal adenocarcinoma, and PanIN lesions can mimic infiltrating cancer.

Background: The gene expression profile of pancreatic cancer is significantly different from that of normal pancreas. Differences in gene expression are detectable using microarrays, but microarrays have traditionally been applied to pancreatic cancer tissue obtained from surgical resection. We hypothesized that gene expression alterations indicative of pancreatic cancer can be detected by profiling the RNA of pancreatic juice. Methods: We performed oligonucleotide microarray analysis on RNA isolated from pancreatic juice obtained endoscopically after secretin stimulation from six patients with pancreatic cancer and ten patients with nonneoplastic diseases of the pancreas or upper gastrointestinal tract. Extracted RNA was subjected to two rounds of linear RNA amplification, and then hybridized with U133A or X3P gene chips (Affymetrix). Results: Using the U133A or X3P chips, 37 and 133 gene fragments respectively, were identified as being at least 3-fold more abundant in the pancreatic juice of patients with pancreatic cancer compared to the noncancer controls ( p < 0.05, Mann-Whitney test). For example, pancreatic juice from patients with pancreatic cancer contained increased levels of IL8, IFITM1, fibrinogen, osteopontin, CXCR4, DAF and NNMT RNA, genes that have been previously reported as overexpressed in primary pancreatic cancers or pancreatic cancer cell lines relative to control tissues. Conclusions: These results demonstrate that RNA analysis of pancreatic juice can reveal some of the same RNA alterations found in invasive pancreatic cancers. RNA analysis of pancreatic juice deserves further investigation to determine its utility as a tool for the evaluation of pancreatic lesions.

BACKGROUND. The p53-dependent G2/M checkpoint plays a key role in the maintenance of genomic integrity, thereby protecting cells from neoplastic progression. Reprimo, a gene involved in the p53-induced G2 cell cycle arrest, has been recently identified as a novel target for aberrant methylation in pancreatic and other cancers. The biological and clinical relevance of Reprimo methylation in pancreatic cancer was investigated.METHODS. The methylation status of Reprimo CpG island was analyzed by methylation-specific polymerase chain reaction in a large series of pancreatic cancers and was correlated with p53 mutation status, genetic instability (as measured by the fractional allelic loss), and clinicopathologic features.RESULTS. Aberrant methylation of Reprimo was identified in 60% (75 of 125) of pancreatic cancer xenografts and primary pancreatic adenocarcinomas. Reprimo methylation was also detectable in 30% (19 of 63) of pancreatic intraepithelial neoplasias (PanIN), known precursors to infiltrating carcinoma. Reprimo methylation was unrelated to the p53 mutation status and associated with the increased degree of genetic instability (P=.04). Furthermore, we found that patients with Reprimo methylation in their primary pancreatic cancers have significantly worse prognosis than those without Reprimo methylation (P=.007). In contrast, other methylation targets in pancreatic cancers (SPARC and CXCR4) did not correlate with prognosis.CONCLUSIONS. These results suggest that aberrant methylation of Reprimo is a common event in pancreatic carcinogenesis and is associated with genetic instability and unfavorable outcome after surgical resection.

Background & Aims: Recently described genome-wide approaches robustly detect many candidate genes that are regulated by DNA methylation, but many of these genes do not represent important targets for functional inactivation. Here we used a microarray-based strategy to identify biologically relevant genes associated with epigenetic silencing in pancreatic cancer. Methods: We compared information from differential gene expression analysis with the transcriptional responses to epigenetic modifiers. Results: Using this approach, we identified 7 novel targets for aberrant methylation in pancreatic cancer. One of the genes identified, RELN (Reelin), a key regulator of neuronal migration, is frequently silenced in pancreatic cancers, as are several of its downstream mediators. Importantly, small interfering RNA-mediated knockdown of RELN in pancreatic cancer cells that retain RELN expression resulted in greatly enhanced cell motility, invasiveness, and colony-forming ability. Increased cell motility was also induced by knockdown of downstream components of the RELN pathway, including ApoER2, VLDLR, and DAB1. Treatment of pancreatic cancer cells with histone deacetylase inhibitors, valproic acid and suberoylanilide hydroxamic acid, restored the expression of RELN and DAB1 and markedly inhibited their migration. Conclusions: The high prevalence of the silencing of RELN pathway components and its reversal by histone deacetylase inhibitors suggest the importance of this pathway as a diagnostic and therapeutic target for pancreatic cancer.

Now that more than two decades have passed since the first reports of intraductal papillary-mucinous neoplasms (IPMNs), it has become clear that IPMN consists of a spectrum of neoplasms with both morphological and immunohistochemical variations. At a meeting of international experts on pancreatic precursor lesions held in 2003, it was agreed that a consensus classification of IPMN subtypes should be established to enable a more detailed analysis of the clinicopathological significance of the variations. Based on our experience and on information from the literature, we selected representative histological examples of IPMNs and defined a consensus nomenclature and criteria for classifying variants as distinctive IPMN subtypes including gastric type, intestinal type, pancreatobiliary type, and oncocytic type. These definitions can be used for further analyses of the clinicopathological significance of the variations of IPMN.

Purpose: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is an increasingly identified precursor to infiltrating ductal adenocarcinoma. Although our knowledge of the clinical and pathologic features of IPMNs is increasing, the molecular mechanisms underlying these neoplasms remain poorly understood. Experimental Designs: To provide further insight into the molecular pathobiology of IPMNs, global expression profiling was done to determine genes that are inactivated/down-regulated in IPMNs using oligonucleotide microarrays (Affymetrix). Results: In total, 300 unique transcripts (217 known genes) were identified as highly underexpressed in 12 IPMNs (< 10-fold lower and P < 0,05) compared with five normal pancreatic ductal epithelium samples obtained by laser capture microdissection. The differential expression of a selection of genes was confirmed using reverse-transcription PCR. One of the genes underexpressed at both the transcriptional and protein level in a significant proportion of IPMNs was the cyclin-dependent kinase inhibitor, CDKN1C/p57K1P2. CDKN1C expression was also decreased in many pancreatic cancer cell lines and was restored following treatment with a DNA methylation inhibitor (5-aza-2'-deoxycitidine) or, more potently, with a histone deacetylase inhibitor (trichostatin A), Partial methylation of the CDKN1C promoter CpG island was found in most, but not all, pancreatic cancer cell lines with reduced CDKN1C expression, and was also detectable in IPMNs. Furthermore, a subset of pancreatic cancers showed complete hypornethylation of LIT1, an imprinting control region important for the regulation of CDKN1C expression. Complete hypornethylation in these cancers was the result of deletion of the methylated LIT1 allele at 11p15.5 rather than loss of imprinting. dConclusions: These findings suggest that CDKN1C is commonly down-regulated in pancreatic ductal neoplasms through a combination of promoter hypermethylation, histone deacetylation, and loss of the maternal allele expressing CDKN1C.