AimThere is some evidence that von Meyenburg complexes (VMCs) can progress to cholangiocarcinoma (CC). This study aimed to evaluate the prevalence of VMCs in CC cases.MethodsAll hepatic resections and explants with intra-hepatic CC (I-CC) and hilar-CC (H-CC) from 1985 to 2020 were studied. Hepatic resections (n=68) for benign lesions or metastatic colonic carcinoma and 15 cases with cirrhosis without any cancer were used as controls.ResultsA total of 118 cases of CC (88 I-CC, 30 H-CC) were identified. Of these, 61 (52%) patients had no known background liver disease, and 20 (17%) had cirrhosis. Associated liver disorders included metabolic dysfunction-associated steatohepatitis (23), chronic viral hepatitis B or C (13), biliary disease (primary or secondary sclerosing cholangitis) (8), polycystic kidney disease (6), cryptogenic cirrhosis (5) and others miscellaneous disorders (7). VMCs were present in 34 (39%) of 88 I-CC cases and 7 (23%) of 30 H-CC cases. VMCs were present within the tumour (20 cases), outside the cancer (21 cases) or at both locations (10 cases). VMCs with dysplasia/carcinoma in situ were seen in 19 of 41 (46%) cases with CC and VMCs. In addition, bile duct adenomas were identified in 6 (5%) of CC. 7% of controls showed the presence of VMCs compared with 35% of CC cases (p<0.05).ConclusionsVMCs are seen far more frequently in patients with CC than in the control group. The findings support the hypothesis that VMCs could represent a precursor of CC or a marker for a higher risk of developing CC.

A variety of cystic and fibrocystic lesions can occur in the liver, which may be single or multiple and etiologically can be acquired or have genetic underpinnings. Although the morphology of ductal plate development and various associated malformations has been well described, the genetic etiologies of many of these disorders are still poorly understood. Multiple clinical phenotypes in the liver are proposed to originate from ductal plate malformations: congenital hepatic fibrosis, Caroli's disease, Von Meyenburg complex, and the liver cysts of autosomal dominant polycystic kidney and liver diseases. Although many of the patients with these disorders, particularly with isolated liver involvement remain asymptomatic, some develop portal hypertension or symptoms from cyst enlargement. Development of hepatocellular malignancy is a risk in a small subset. Recent advances have made it now possible for some of these phenotypes to be genetically defined, and intriguingly animal models of adult polycystic liver disease suggest that abnormal organ development is not required. This review describes the current understanding, genetic underpinning, and key clinicopathologic and imaging features of these fibropolycystic liver diseases.

Purpose of review The aim of this study was to summarize the basic epidemiology, pathophysiology and management of delayed serologic and delayed haemolytic transfusion reactions (DHTRs), as well as recent developments in our understanding of these adverse events. Recent findings Several studies have identified risk factors for DHTRs, including high alloantibody evanescence rates among both general patient groups and those with sickle cell disease (SCD). Antibody detection is also hampered by the phenomenon of transfusion record fragmentation. There have also been enhancements in understanding of what may contribute to the more severe, hyperhaemolytic nature of DHTRs in SCD, including data regarding ‘suicidal red blood cell death’ and immune dysregulation amongst transfusion recipients with SCD. With growing recognition and study of hyperhaemolytic DHTRs, there have been improvements in management strategies for this entity, including a multitude of reports on using novel immunosuppressive agents for preventing or treating such reactions. Summary Delayed serologic and haemolytic reactions remain important and highly relevant transfusion-associated adverse events. Future directions include further unravelling the basic mechanisms, which underlie DHTRs and developing evidence-based approaches for treating these reactions. Implementing practical preventive strategies is also a priority.

BACKGROUND: Small intestinal neuroendocrine neoplasm (SI-NEN) proliferation is quantified by Ki67 measurements which capture G1-G2M phases of the cell cycle. G(0) and early G(1) phases, typical of slow-growing cells, can be detected by minichromosome maintenance protein (MCM) expression. We hypothesized that these replication licensing markers may provide clinically relevant information to augment Ki67 in low-grade neuroendocrine neoplasia. METHODS: Immunohistochemical staining (IHC), Western blot analysis, quantitative polymerase chain reaction, and copy number variations of MCM2, MCM3, and Ki67 were undertaken in SI-NENs (n = 22). MCM and Ki67 expression was compared by Kaplan-Meier survival analysis (tissue microarray, independent set [n = 55]). Forty-three pancreatic NENs and 14 normal tissues were included as controls. RESULTS: In SI-NENs, MCM2 (mean: 21.2%: range: 16%-25%) and MCM3 (28.7%: 22%-34%) were detected in significantly more cells than Ki67 (2.3%: 0%-7%, P < .01). MCM2 mRNA correlated with Ki67 IHC (P < .05). MCM3 protein expression was higher in metastases (38-fold) than in normal small intestine (P = .06) and was largely absent in normal neuroendocrine cells. There was considerable variation at the MCM copy number level (0-4 copies). MCM3 expression in proliferating cells significantly predicted overall survival (P < .002). Combinations of Ki67 and MCM2/3 in algorithms differentiated low and higher proliferative lesions (overall survival: 12 vs 6.1 years, P = .06). MCM expression was not informative in pancreatic NENs. CONCLUSION: MCMs are expressed in a higher proportion of NEN cells than Ki67 in slow-growing small intestinal lesions and correlate with survival. Assessment can be used to augment Ki67 to improve prognostic classification in these low-grade tumors.

Significance The identical recurrent somatic heterozygous missense mutation in the DNA-binding domain of transcription factor YY1 is found in a third of insulin-secreting pancreatic tumors. This mutation alters sites involved in DNA contact and changes the DNA sequence motif that is bound, resulting in significant alteration of gene expression. Among genes showing markedly increased expression are two, an adenylyl cyclase ( ADCY1 ) and a Ca 2+ channel ( CACNA2D2 ), that are involved in cAMP and Ca 2+ signaling, processes known to play a role in insulin secretion. Expression of these genes in a pancreatic β-cell line causes increased insulin release. These findings provide evidence for neomorphic effects of this mutation, and demonstrate a role for altered transcription factor specificity in neoplasia.

Despite an overall decrease in colorectal carcinoma incidence, rates of colorectal carcinoma have increased substantially in patients aged less than 40 years. Several authors have characterized morphologic features of colorectal carcinoma in young patients, with variable results. To date, there has been 1 detailed molecular and immunohistochemical study in young patients with colorectal carcinoma. We sought to expand the data regarding young patients with colorectal carcinoma by a detailed assessment of morphologic features and by assaying expression of p27, COX-2, MLH1, and MSH2, markers with prognostic or therapeutic implications in colorectal carcinoma. We searched our pathology database from 1985 to 2009 and, after exclusion of cases with insufficient data or neoadjuvant therapy, identified a study population of 23 patients aged 40 or younger, 35 patients between 41 and 49 years of age, and a control group of 83 colorectal carcinoma patients aged 50 or older. Younger patients had higher tumor grade (P = .0085), with a trend toward mucinous differentiation and lymphovascular and perineural invasion. Loss of MSH2 was more prominent in younger patients (P = .02). Loss of p27 expression was not associated with age, but was associated with higher tumor stage (P = .0278), mucinous/signet ring differentiation (P = .0185), loss of either MLH1 or MSH2 (P = .0035), and larger tumor size (P = .0019). There was a trend toward lower COX-2 expression in younger patients, with less COX-2 expression relative to previously published data. Our findings support some prior reports regarding morphologic features in colorectal carcinoma in young patients and provide novel data on expression of several markers in this population.

Background Accurate neuroendocrine neoplasia (NEN) staging is vital for determining prognosis and therapeutic strategy. The great majority of NENs express chromogranin A (CgA) which can be detected at a protein or transcript level. The current standards for lymph node metastasis detection are histological examination after Hematoxylin and Eosin (H&E) and CgA immunohistochemical (IHC) staining. We hypothesized that detection of CgA mRNA transcripts would be a more sensitive method of detecting these metastases. Findings We compared these traditional methods with PCR for CgA mRNA extracted from formalin fixed paraffin embedded slides of lymph nodes ( n = 196) from small intestinal NENs, other gastrointestinal cancers and benign gastrointestinal disease. CgA PCR detected significantly more NEN lymph nodes (75%) than H&E (53%) or CgA IHC (57%) ( p = 0.02). PCR detected CgA mRNA in 50% (14 of the 28) of SI-NEN lymph nodes previously considered negative. The false positive rate for detection of CgA mRNA was 19% in non-neuroendocrine cancers, and appeared to be due to occult neuroendocrine differentiation or contamination by normal epithelium during histological processing. Conclusions Molecular pathological analysis demonstrates the limitations of observer-dependent histopathology. CgA PCR analysis detected the presence of CgA transcripts in lymph nodes without histological evidence of tumor metastasis. Molecular node positivity (stage mol N1) of SI-NEN lymph nodes could confer greater staging accuracy and facilitate early and accurate therapeutic intervention. This technique warrants investigation using clinically annotated tumor samples with follow-up data.

Clinical Practice Points •Large cell neuroendocrine carcinoma (LCNEC) is recognized as a distinct subset of neuroendocrine tumors defined by poorly differentiated morphologic characteristics and expression of the classic neuroendocrine markers synaptophysin and chromogranin. LCNEC can occur in diverse locations; regardless of the location this tumor is generally associated with an aggressive clinical course and poor outcome. Most neuroendocrine tumors of the stomach are low grade, but gastric LCNEC (GLCNEC) has been described and behaves similarly to LCNEC at other sites. In patients with rapidly proliferating tumors (high Ki-67 index), fluorine-18( 18 Lawrence B. Kidd M. Svejda B. et al. A clinical perspective on gastric neuroendocrine neoplasia. Curr Gastroenterol Rep. 2011; 13: 101-109 Crossref PubMed Scopus (29) Google Scholar F) fluorodeoxyglucose–positron emission tomography (FDG-PET) is an important tool for diagnosis. Because of the rarity of these tumors, prompt diagnosis of GLCNEC may be challenging and requires a high index of suspicion. •We report here a case of GLNEC that presented with a large gastric mass with multiple octreotide-avid liver lesions. The tumor was high grade and positive for neuroendocrine markers. GLCNEC was diagnosed and the patient was treated with platinum-based combination chemotherapy with carboplatin/paclitaxel as well as long-acting release octretide. The patient had a good clinical and radiographic response to therapy, but bone metastasis subsequently developed and the patient died of disease progression. •GLCNEC is an emerging pathologic diagnosis and describes a high-grade tumor with an aggressive course. Awareness of this diagnosis and prompt treatment with platinum-based chemotherapy as well as supportive care may provide clinical benefit. Further trials are needed to define the optimal chemotherapeutic regimen and the role of somatostatin analogues in appropriate patients. •Large cell neuroendocrine carcinoma (LCNEC) is recognized as a distinct subset of neuroendocrine tumors defined by poorly differentiated morphologic characteristics and expression of the classic neuroendocrine markers synaptophysin and chromogranin. LCNEC can occur in diverse locations; regardless of the location this tumor is generally associated with an aggressive clinical course and poor outcome. Most neuroendocrine tumors of the stomach are low grade, but gastric LCNEC (GLCNEC) has been described and behaves similarly to LCNEC at other sites. In patients with rapidly proliferating tumors (high Ki-67 index), fluorine-18( 18 Lawrence B. Kidd M. Svejda B. et al. A clinical perspective on gastric neuroendocrine neoplasia. Curr Gastroenterol Rep. 2011; 13: 101-109 Crossref PubMed Scopus (29) Google Scholar F) fluorodeoxyglucose–positron emission tomography (FDG-PET) is an important tool for diagnosis. Because of the rarity of these tumors, prompt diagnosis of GLCNEC may be challenging and requires a high index of suspicion. •We report here a case of GLNEC that presented with a large gastric mass with multiple octreotide-avid liver lesions. The tumor was high grade and positive for neuroendocrine markers. GLCNEC was diagnosed and the patient was treated with platinum-based combination chemotherapy with carboplatin/paclitaxel as well as long-acting release octretide. The patient had a good clinical and radiographic response to therapy, but bone metastasis subsequently developed and the patient died of disease progression. •GLCNEC is an emerging pathologic diagnosis and describes a high-grade tumor with an aggressive course. Awareness of this diagnosis and prompt treatment with platinum-based chemotherapy as well as supportive care may provide clinical benefit. Further trials are needed to define the optimal chemotherapeutic regimen and the role of somatostatin analogues in appropriate patients.

The risks of transfusion remain significant. Familiarity with the incidence, etiology, management, and prevention of commonly encountered transfusion reactions is integral to the practice of transfusion medicine. This review intends to serve as a practical guide reflecting the current understanding of adverse transfusion events, clinical features helpful for diagnosis, and recommended management strategies for typical scenarios. Severe and mild transfusion reactions are covered, with a focus on the distinguishing features of challenging clinical dilemmas. Topics include pulmonary complications of transfusion, hemolytic reactions, allergic and anaphylactic reactions, septic reactions, and febrile responses to transfusion. We also discuss a consultative approach to evaluation and reporting of transfusion reactions.

Angiogenesis is one of the hallmarks of tumor growth and metastasis. Identification of tumor angiogenic factors has been a critical component in understanding cancer biology and treatment. Intermedin (IMD) has been reported to promote angiogenesis in a rat ischemic model and human umbilical vascular endothelial cells. Our study sought to determine the role of IMD in human hepatocellular carcinoma tumor progression. High IMD mRNA expression levels were observed in human hepatocellular carcinoma tumors, even in early stage disease, by real‐time RT‐PCR. Immunohistochemical analysis of hepatocellular carcinoma clinical samples demonstrated that the tumor regions were significantly more immunoreactive for IMD than adjacent benign liver. Inhibition of IMD expression using RNA interference reduced cell proliferation in SK‐Hep‐1 and SNU‐398 cells. Blockage of IMD signaling using either an antagonist peptide or a neutralizing antibody inhibited growth in a dose‐dependent manner with concomitant induction of apoptosis, causing cleavage of caspase‐8 and downregulation of Gli1 and Bcl2. Conversely, addition of IMD active peptide increased the phosphorylation level of extracellular signal‐regulated kinase. Thus, IMD might play an important role in cell proliferation and survival of hepatocellular carcinoma. Our data suggests that IMD is a potential biomarker and therapeutic target for hepatocellular carcinoma. ( Cancer Sci , doi: 10.1111/j.1349‐7006.2012.02341.x, 2012)

We searched the surgical pathology database for cases of PENs that were surgically resected at our institution from January 1998 to June 2011. A total of 58 cases were included and constructed for a TMA in which two 1-mm representative core tissue fragments from the tumor and corresponding non-neoplastic pancreatic tissue were included for each case. Immunohistochemistry was performed on TMA sections using antibodies against PAX8, NeuroD1, survivin, CD44 and Ki-67 with appropriate positive and negative controls. Expression of PAX8, NeuroD1, survivin, CD44 and Ki-67 was evaluated and semi-quantified. Nuclear staining for PAX8, NeuroD1 and Ki-67, cytoplasmic/nuclear staining for survivin, and cytoplasmic/membranous staining for CD44 were considered positive if >2% (for Ki-67) or >5% (for other markers) of the cells stained. Fisher's exact Chi-square analysis and Chisquare test for trend, where appropriate, were performed to correlate expression of these markers with the following: tumor functional status, lymph node metastasis, liver metastasis, and WHO classification. The markers significant on univariate analysis were included in exact logistic regression models. CONCLUSIONS

242 Background: Ki-67 is the major proliferative marker in clinical use to determine neuroendocrine neoplasm (NEN) prognosis. Ki-67 is unable to predict the outcome of SI-NENs, as the majority have a low (≤2) Ki-67%. Therefore, we aimed to identify a sensitive panel of proliferative markers using qRT-PCR to more accurately define the proliferation of these slow growing tumors. Methods: We identified genes with a mechanistic function in cell cycle progression that were over-expressed in RNA microarrays of SI-NENs (n=8) compared to adjacent normal tissue (n=4) (dCHIP, annotation databases). Timing of marker gene expression (qRT-PCR) in proliferating cell-cycle phases (S, G 2 , M) was determined in flow-sorted SI-NEN cell lines (KRJ-1, H-STS) after propidium iodide staining. RNA expression of candidate proliferative markers was then investigated using an in vivo model and two independent tumor datasets, and transcript level compared to Ki-67% protein expression (immunohistochemical staining). Results: Twenty genes with a mechanistic role in proliferation were identified and 17 confirmed to be expressed in proliferating cell cycle phases. Each tumor expressed a unique profile of the 17 proliferative markers. Both Ki-67 protein and Ki-67 RNA transcript levels failed to differentiate in vivo SI-NEN models or patient samples despite variable proliferative capacity (e.g., WDNETs versus WDNECs). Although most tumors showed low levels of Ki-67 expression, the tumors expressed high levels of select alternative proliferative markers. Hierarchical clustering provided a novel and clinically meaningful prognostic classification. Conclusions: Proliferation of individual SI-NENs is regulated by unique combinations of multiple genes with a mechanistic role in cell-cycle progression. Regulation of proliferation in SI-NENs is therefore complex and cannot accurately be defined by Ki-67 as a single marker. A panel of proliferative RNA markers has potential to significantly improve prognostication in patients with SI-NENs.

Congenital diaphragmatic hernia (CDH) is associated with multiple congenital anomalies affecting several organ systems, including the gastrointestinal system. Pyloric stenosis and bands are known and previously reported etiologies of gastric outlet obstruction in infants with CDH. We report the first case of gastric antrum hypertrophy causing gastric outlet obstruction in an infant with CDH.

Introduction Wagner-Meissner corpuscles (WMCs) are Schwannianderived specialized nerve endings typically found in the dermal papillae of glabrous skin (ie, hairless skin found on the plantar and palmar surfaces), where they function as mechanoreceptors. Previous reports in the literature have used a multitude of terms (tactile corpuscle-like bodies, tactoid bodies, Wagner-Meissner bodies, pseudoMeissner corpuscles, and Meissneroid corpuscles) to describe morphologically identical structures found outside this normal histological realm. WMCs have been recognized as a minor component in some benign neural neoplasms, including neurofibromas, schwannomas, and cellular nevi. Lesions composed predominantly of WMCs have also been infrequently described in several locations, including the vulva, cheek, periaortic tissue, finger, and lower extremity. It is important to note that although WMCs are incidentally identified in a variety of tissues in histological sections and occasionally in the above-mentioned neoplasms, they are not seen normally in the lamina propria of the gastrointestinal (GI) tract. We report 2 patients with colonic polyps composed entirely of S100-positive spindle cells with differentiation toward WMC. This unique morphology was initially a cause of diagnostic confusion. Awareness of this entity may prevent mischaracterization with other types of unusual colon polyps. Additionally, in our experience, we believe that these lesions, in isolation, should not raise clinical concern for a syndromic association, which may otherwise be elicited given their neural origin and distinct morphology.

Intraductal papillary mucinous neoplasms constitute histologically distinctive pancreatic tumors characterized by cystically dilated pancreatic ducts lined by papillary epithelium, often with extensive mucin production. With increasing awareness of and vigilance for these tumors, there has been a surge in the incidence of intraductal papillary mucinous neoplasms in the last few decades. However, resections of presumed intraductal papillary mucinous neoplasms sometimes reveal other types of cystic lesions. Here we describe 3 cases of small, incidentally identified pancreatic endocrine tumors that focally compressed the main pancreatic duct and presented clinically, radiologically, and grossly as intraductal papillary mucinous neoplasm. The histology of the dilated ducts in all cases lacked convincing features of intraductal papillary mucinous neoplasm, prompting more careful examination of the specimens and eventual identification of small well-differentiated endocrine neoplasms. The constellation of findings represented by pancreatic endocrine neoplasm–associated duct stricture and dilatation can mimic intraductal papillary mucinous neoplasm clinically and pathologically. Awareness of this phenomenon can potentially avoid misdiagnosis of intraductal papillary mucinous neoplasm in such cases.

Primary peritoneal carcinoma (PPCa) is a relatively uncommonly diagnosed tumor. It has a similar presentation to ovarian cancer. PPCa has a poor prognosis with survival ranging from 12-18 months. PPCa spreads mainly transperitoneally, but lymphatic and hematological metastases have also been reported. It is a diagnosis of exclusion made after pathological report. Here, a case of a 71-year-old female who presented with early satiety, fatigue, weight loss and left cervical lymphadenopathy and was diagnosed with metastatic PPCa, is reported. The patient was treated with chemotherapy and achieved a complete remission. The management of this rare tumor is discussed herein.

Abstract Intermedin (IMD) functions as an angiogenic factor in a rat ischemic model and human endothelial cells. In our search for anti-angiogenic therapy for solid tumors, we analyzed the expression and possible role of IMD in tumor angiogenesis. IMD was expressed in human colorectal adenocarcinoma (CRC) and hepatocellular carcinoma (HCC). The IMD expression was significantly higher in stage I than stage 0 of both colon and liver tumors (stage I/0 ratio of mRNA level is 7.7 ± 0.4 and 3.2 ± 0.3, respectively). IMD was widely expressed in colon and liver tumor lines. Immunohistochemistry showed that the tumor regions were significantly more immunoreactive for IMD than adjacent benign regions of CRC and HCC specimens. Inhibition of IMD expression by RNA interference reduced cell proliferation by 29.7 ± 6.7% (n = 3, p = 0.047) and impaired cell invasion by 27.8 ± 3.6% (n = 3, p = 0.016) in a HCC cell line SK-Hep-1. Addition of IMD peptide for 5 minutes to serum starved SK-Hep-1 cells increased the phosphorylation level of p44 and p42 MAP Kinase (Erk1/2), suggesting that IMD regulates Sk-Hep-1 cell growth, at least partly, through activating Erk1/2 signaling pathway. Similarly, IMD knockdown in a CRC cell line HCT116 reduced cell growth by 35.0 ± 1.4 % (n = 3, p = 0.018). Conditioned medium from IMD siRNA-transfected SK-Hep-1 cells reduced endothelial cell tube formation by 31.6 ± 6.8%. Conversely, over-expression of IMD in CRC RKO cells increased cell growth and induced cell migration significantly. Furthermore, treatment with RKO/IMD conditioned medium increased endothelial cell tube formation by 14. 7 ± 0.8% (n=4, p = 0.049). Thus, IMD stimulated HCC and CRC cell growth, migration, and invasion, indicating a role for IMD in tumor angiogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5149. doi:10.1158/1538-7445.AM2011-5149