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Background: The accuracy and costs of current diagnostic methods in the differential diagnosis of pancreatic cystic lesions still has ample room for improvement., Aims: The aim of the study was to confirm the diagnostic yield of intracystic glucose in the diagnosis of pancreatic cyst subtypes., Methods: We prospectively recruited all patients who underwent Endoscopic Ultrasound with Fine Needle Aspiration of pancreatic cyst at our Institution., Results: Fifty-six patients were included in the study. We found that intracystic glucose concentration < 50 mg/dL was significantly more sensitive than a concentration of Carcinoembryonic Antigen > 192 ng/mL (93.6% vs 54.8%; p = 0.003) for the diagnosis of mucinous cysts. In terms of specificity, the two markers were not different (96% vs 100%; p = 1). Regarding the diagnosis of non-mucinous cysts, intracystic glucose concentration ≥ 50 mg/mL showed higher sensitivity than Carcinoembryonic Antigen level < 5 ng/mL (96% vs 72%) although a statistical significance could not be reached (p = 0.07). The two markers were not statistically different in terms of specificity (93.6% vs 87.1%; p = 0.62)., Conclusion: Given its diagnostic performance and ease of measurement, intracystic glucose may replace Carcinoembryonic Antigen in the differential diagnosis of mucinous versus non-mucinous pancreatic cysts., Competing Interests: Declaration of Competing Interest Claudio De Angelis is consultant for Boston Scientific., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: The tissue acquisition and diagnostic yield of cyst fluid cytology is low-to-moderate and rarely provides a specific diagnosis. The aim of this study was to compare the tissue acquisition and diagnostic tissue yield of microforceps biopsy (MFB) with cyst fluid cytology., Methods: In this multicenter study, data of 42 patients who had cysts both aspirated by EUS-guided FNA (EUS-FNA) and biopsy specimens were then obtained with an MFB device, were collected. Cytology analysis of cyst fluid and histologic analysis of biopsy specimens were done. Acquisition yield was defined as percentage of patients with tissue present in the aspirate or biopsy. Diagnostic tissue yield was evaluated at 3 levels: the ability of differentiation between mucinous and/or nonmucinous cysts, detection of high risk for malignancy, and specific cyst type diagnosis., Results: The mean patient age was 69 years. Sixteen pancreatic cysts (38.1%) were located in the head, 17 (40.5%) in the body, and 9 (21.4%) in the tail. The mean cyst size was 28.2 mm (12-60 mm); 25 of 42 (60%) were septated. The EUS-FNA tissue (fluid) acquisition yield was 88.1% (37/42). The MFB tissue acquisition yield was 90.4% (38/42). The diagnostic cytology yield to differentiate between mucinous and/or nonmucinous cysts was 47.6% (20/42), and the MFB histologic yield to differentiate between mucinous and/or nonmucinous cysts was 61.9% (26/42) (P = .188). The percentage of cysts at high risk for malignancy by cytology was 54.7% (23/42), and MFB was 71.5% (30/42) (P = .113). However, the ability of MFB to provide a specific cyst type diagnosis was 35.7% (15/42), and that for cytology was 4.8% (2/42) (P = .001). Surgical histology was concordant with that of MFB in 6 of 7 patients (85%), and with that of cytology in 1 of 7 patients (15%)., Conclusion: The cyst tissue acquisition yield for MFBs was 90%. Although cytology of cyst fluid and MFB were comparable in distinguishing mucinous and nonmucinous cysts and detecting cysts at high risk for malignancy, MFB was far superior to cytology for providing a specific cyst diagnosis., (Published by Elsevier Inc.)

Mucins are heavily glycosylated proteins overexpressed and associated with truncated or sialylated glycans upon malignant transformation. We previously identified a panel of four glyco-mucin profiles (MUC16/Tn, MUC16/STn, MUC1/Tn, and MUC1/STn) with 100 % specificity and 100 % positive predictive value for detection of borderline/malignant serous tumors of the ovary, using proximity ligation assay (PLA). In the present work, using the same method, we studied other mucin glycosylation profiles that might add relevant information for diagnostic purposes. We used PLA probes to MUC16, MUC1, sialyl Lewis(a) (SLe(a)), and sialyl Lewis(x) (SLe(x)) to study a series of 39 ovarian serous tumors (14 adenocarcinomas, 10 borderline ovarian tumors (BOTs), and 15 cystadenomas). Our results demonstrated that, in adenocarcinomas and BOTs, the major carriers of SLe(a) and SLe(x) are MUC16 and/or MUC1 (100 and 92 % for SLe(a) and 64 and 70 % for SLe(x), respectively). In cystadenomas, SLe(a) and SLe(x) are mainly carried by unidentified proteins (85 and 78 %, respectively). Our study identified, for the first time, the major protein carriers of SLe(a) and SLe(x) in ovarian adenocarcinomas and BOTs, MUC1 and MUC16, and also that distinct unidentified carriers are involved in cystadenomas. These results emphasize the relevance of multiple biomarker recognition provided by multiplex assays, such as PLA, to enhance sensitivity and specificity of serum and tissue assays.

Background and Aims: The value of next-generation sequencing (NGS) of pancreatic cyst fluid relative to the clinical and imaging impression has not been well-studied. The aim of this study was to assess the impact of NGS on the clinical diagnosis from imaging and carcinoembryonic antigen (CEA) and thus the management of pancreatic cysts., Methods: Ninety-two pancreatic cyst fluids from 86 patients were analyzed by cytology, CEA, and targeted NGS. Cysts were classified by imaging as nonmucinous, mucinous, or not specified. NGS results were compared with the imaging impression stratified by CEA and cytology., Results: NGS impacted the clinical diagnosis by defining a cyst as mucinous in 48% of cysts without elevated CEA levels. The VHL gene in 2 intraductal papillary mucinous neoplasms (IPMNs) supported a serous cystadenoma. Twenty percent of cysts that were nonmucinous by imaging were mucinous by NGS. Of the 14 not-specific cysts, CEA levels were not elevated in 12 (86%), and NGS established a mucinous etiology in 3 (25%). A KRAS or GNAS mutation supported an IPMN with nonmucinous CEA in 71%. A KRAS mutation reclassified 19% of nonneoplastic cysts with nonmucinous CEA as mucinous. Seven cyst fluids (8%) had either a TP53 mutation or loss of CDKN2A or SMAD4 in addition to KRAS and/or GNAS mutations; 5 of 7 (71%) were clinically malignant, and high-grade cytology was detected in all 5. Overall, CEA was more specific for a mucinous etiology (100%), but NGS was more sensitive (86% vs 57%)., Conclusions: NGS of pancreatic cyst fluid impacts clinical diagnosis and patient management by defining, supporting, or changing the clinical diagnosis based on imaging and CEA. NGS was most valuable in identifying mucinous cysts with nonmucinous CEA. An added benefit is the potential to detect mutations late in the progression to malignancy that may increase the risk classification of the cyst based on imaging and cytology., (Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Cystadenomas of the liver and extrahepatic bile ducts (EHBD) are uncommon but distinctive neoplasms whose terminology and epithelial phenotype have been a source of controversy. We reviewed 20 cases, 16 arising in the liver and 4 in the EHBD. Eighteen patients were women, with a mean age of 36.5 years. Eighteen tumors were multiloculated and 2 were unilocular. The tumor size ranged from 4 to 29 cm (average, 11 cm). The cyst fluid in 13 tumors was described as serous, in 2 as clear, in 2 others as hemorrhagic, and in 1 as serous and mucinous. Only in 2 tumors was the fluid described as mucinous. In 18 cystadenomas, the predominant epithelial lining consisted of a single layer of cuboidal or low-columnar nondysplastic cells similar to those of the gallbladder or bile ducts. This epithelial lining was strongly positive for cytokeratins 7 and 19, and focally positive for MUC1. Only 2 cystadenomas showed predominant intestinal differentiation characterized by mature goblet cells and columnar absorptive cells. These cells expressed CDX2, MUC2, and cytokeratin 20. Admixed with the goblet and columnar cells, there were serotonin-containing cells and Paneth cells. These 2 tumors showed extensive areas of high-grade dysplasia and invasive adenocarcinoma with intestinal phenotype. A subepithelial ovarian-like stroma was present in all tumors. None of the patients died of the tumors. We believe that the term mucinous cystic tumor recommended by the World Health Organization for all cystadenomas of the liver and EHBD is a misnomer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Human METCAM/MUC18 (huMETCAM/MUC18), a cell adhesion molecule, plays an important role in the progression of several epithelial cancers; however, its role in the progression of epithelial ovarian cancers is unknown. To initiate the study we determined expression of this protein in normal and cancerous ovarian tissues, cystadenomas, metastatic lesions, and ovarian cancer cell lines., Materials and Methods: Immunoblotting and immunohistochemical (IHC) methods were used to determine huMETCAM/MUC18 expression in lysates of frozen and formalin-fixed, paraffin-embedded tissue sections of normal human ovaries, and ovarian (benign) cystadenomas, carcinomas and metastatic lesions. We also determined expression levels of several downstream effectors of METCAM/MUC18 in these tissues., Results: HuMETCAM/MUC18 levels in ovarian carcinomas and metastatic lesions were significantly higher than in normal tissues and cystadenomas. IHC results showed that expression of huMETCAM/MUC18 in normal tissues and cystadenomas was mostly absent from epithelial cells, but in carcinomas and metastatic lesions it was localized to epithelial cells. In higher pathological grades of ovarian cancer and metastatic lesions, the percentage of cells stained in IHC was increased. Thirty percent of normal tissues weakly expressed the huMETCAM/MUC18 antigen, but 70% of cancer tissues and 100% of metastatic lesions expressed the antigen. Expression levels of several downstream effectors of huMETCAM/MUC18, Bcl2, PCNA and VEGF, were elevated in cancerous tissues, however, not that of Bax. The phospho-AKT/AKT ratio was elevated in metastatic lesions., Conclusion: Upexpression of huMETCAM/MUC18 may be a marker for the malignant potential of ovarian carcinomas. Progression of ovarian cancer may involve increased signaling in anti-apoptosis, proliferation, survival/proliferation pathway, and angiogenesis., (Copyright © 2014. Published by Elsevier B.V.)

Biliary cystadenoma (BCA) and biliary cystadenocarcinoma (BCAC) are rare biliary duct neoplasms. This study investigated reasonable management strategies of cystic neoplasms in the liver. Charts of 39 BCA/BCAC patients (9 males, 30 female; median age 53.74 ± 14.50 years) who underwent surgery from January 1999 to December 2009 were reviewed retrospectively. Cyst fluid samples of 32 BCA/BCAC patients and 40 simple hepatic cyst patients were examined for the tumor markers carbohydrate associated antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). The most frequent symptoms were abdominal pain (N = 10), abdominal mass (N = 7), abdominal distension (N = 4), jaundice (N = 2), and fever (N = 3); the remaining patients showed no clinical symptoms. Liver resection (N = 17) or enucleation (N = 22) was performed in the 39 patients. Ultimately, 35 patients were diagnosed with intrahepatic BCA and four patients were diagnosed with BCAC. The median CA19-9 level was significantly higher in BCA/BCAC patients than in simple hepatic cyst patients. The median CEA levels in BCA/BCAC patients and controls were 6.83 ± 2.43 and 4.21 ± 2.91 mg/L, respectively. All symptoms were resolved after surgery, and only one BCAC patient showed recurrence. The incidence of intrahepatic cystic lesions was 1.7%. Increased CA19-9 levels in the cyst fluid is a helpful marker for distinguishing BCA/BCAC from common simple cysts. The presence of coarse calcifications is suggestive of BCAC. Complete surgical removal of these lesions yielded satisfying long-term outcomes with a very low recurrence rate.

The effect of tumor necrosis factor-alpha (TNF-α) gene delivery has been suggested as a potentially useful therapeutic approach to improve the chemotherapeutic treatment of patients with pancreatic ductal adenocarcinoma (PDA), but the exact mechanism of its action is not clearly understood. In this study, we analyzed the expression profile of TNF-α in PDA tissue and explored its potential role in fatty acid synthase (FAS) regulation in PDA cells and in fibroblasts. Quantitative real-time polymerase chain reaction was used to examine the expression of TNF-α in PDA, matching adjacent tissues, and benign lesions. Logistic regression models with robust variance were used to analyze the gene expression levels, and Kaplan-Meier survival curves were generated. In vitro, we overexpressed the TNF-α gene in PDA cells and fibroblasts and analyzed its effect on cell survival, migration, and on members of the FAS signaling pathway. We also evaluated TNF-α effects on a panel of inflammation-, angiogenesis-, and metastasis-related markers. In the tumor tissue of PDA patients, compared with their matched adjacent tissue, expression levels of TNF-α were not statistically different and did not correlate with survival or any other examined clinicopathological features. Overexpression of TNF-α significantly (p < 0.05) reduced PDA and fibroblast cell migration. In PDA cells that highly overexpress TNF-α, this was associated with a significant reduction of FAS mRNA and protein expression levels and significant (p < 0.05) reduction of SREBP-1 and ACC mRNA. Reduction of FAS by TNF-α was inhibited when either SREBP-1 or ACC was knocked down by siRNA. PDA cells and fibroblasts that overexpress TNF-α displayed differential regulation of several inflammation-related markers and reduced levels of metastasis-related genes. Our data demonstrate a previously unknown multi-targeted involvement of TNF-α in PDA lipogenesis and inflammation and metastasis and suggest that intratumoral introduction of TNF-α may have the potential as a novel therapeutic approach in human PDA.

Introduction: Elafin is an endogenous serine protease inhibitor. The majority of breast cancer cell lines lack elafin expression compared to human mammary epithelial cells. In this study, we hypothesized that elafin is downregulated during breast and ovarian tumorigenesis., Methods: We examined elafin expression by immunohistochemistry (IHC) in specimens of normal breast tissue (n = 24), ductal carcinoma in situ (DCIS) (n = 54), and invasive breast cancer (n = 793). IHC analysis of elafin expression was also performed in normal fallopian tube tissue (n = 20), ovarian cystadenomas (n = 9), borderline ovarian tumors (n = 21), and invasive ovarian carcinomas (n = 216). To understand the significance of elafin in luminal breast cancer cell lines, wild-type or M25G elafin (lacking the protease inhibitory function) were exogenously expressed in MCF-7 and T47D cells., Results: Elafin expression was downregulated in 24% of DCIS and 83% of invasive breast tumors when compared to elafin expression in the normal mammary epithelium. However, the presence of elafin-positive cells in invasive breast tumors, even at low frequency, correlated with poor recurrence-free survival (RFS), reduced overall survival (OS), and clinicopathological markers of aggressive tumor behavior. Elafin-positive cells were an especially strong and independent prognostic marker of reduced RFS in IHC-defined luminal A-like tumors. Elafin was also downregulated in 33% of ovarian cystadenomas, 43% of borderline ovarian tumors, and 86% of invasive ovarian carcinomas when compared to elafin expression in the normal fallopian tube. In ovarian tumors, elafin-positive cells were correlated with reduced RFS, OS and disease-specific survival (DSS) only in stage I/II patients and not in stage III/IV patients. Notably, exogenous expression of elafin or elafin M25G in the luminal breast cancer cell lines MCF-7 and T47D significantly decreased cell proliferation in a protease inhibitory domain-independent manner., Conclusions: Elafin predicts poor outcome in breast and ovarian cancer patients and delineates a subset of endocrine receptor-positive breast cancer patients susceptible to recurrence who could benefit from more aggressive intervention. Our in vitro results suggest that elafin arrests luminal breast cancer cells, perhaps suggesting a role in tumor dormancy.

Background: Better pancreatic cyst fluid biomarkers are needed., Objective: To determine whether metabolomic profiling of pancreatic cyst fluid would yield clinically useful cyst fluid biomarkers., Design: Retrospective study., Setting: Tertiary-care referral center., Patients: Two independent cohorts of patients (n = 26 and n = 19) with histologically defined pancreatic cysts., Intervention: Exploratory analysis for differentially expressed metabolites between (1) nonmucinous and mucinous cysts and (2) malignant and premalignant cysts was performed in the first cohort. With the second cohort, a validation analysis of promising identified metabolites was performed., Main Outcome Measurements: Identification of differentially expressed metabolites between clinically relevant cyst categories and their diagnostic performance (receiver operating characteristic [ROC] curve)., Results: Two metabolites had diagnostic significance-glucose and kynurenine. Metabolomic abundances for both were significantly lower in mucinous cysts compared with nonmucinous cysts in both cohorts (glucose first cohort P = .002, validation P = .006; and kynurenine first cohort P = .002, validation P = .002). The ROC curve for glucose was 0.92 (95% confidence interval [CI], 0.81-1.00) and 0.88 (95% CI, 0.72-1.00) in the first and validation cohorts, respectively. The ROC for kynurenine was 0.94 (95% CI, 0.81-1.00) and 0.92 (95% CI, 0.76-1.00) in the first and validation cohorts, respectively. Neither could differentiate premalignant from malignant cysts. Glucose and kynurenine levels were significantly elevated for serous cystadenomas in both cohorts., Limitations: Small sample sizes., Conclusion: Metabolomic profiling identified glucose and kynurenine to have potential clinical utility for differentiating mucinous from nonmucinous pancreatic cysts. These markers also may diagnose serous cystadenomas., (Copyright © 2013 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

We present 5 paratesticular tumors, which manifested ovarian-type stroma and various serous müllerian epithelial structures including serous fallopian-like epithelium and proliferations closely mimicking cystic serous borderline tumors of the ovary. In addition, 3 of the tumors in our series revealed a solid epithelial component, which was morphologically and immunohistochemically similar to so called "female adnexal tumor of probable wolffian origin," which is a rare neoplasm described so far only in the female genital tract, retroperitoneum, and the pelvic cavity. In analogy with mixed epithelial and stromal tumors of the kidney, which are renal neoplasms producing ovarian-type stroma, we suggest to designate the above paratesticular tumors containing ovarian-type stroma as "mixed epithelial and stromal tumors of the paratestis with features of cystic serous borderline tumor" (cases 1 and 2) and "mixed epithelial and stromal tumors of the paratestis with male adnexal tumor of probable wolffian origin" (cases 3-5)., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: It has been suggested that autophagy-related Beclin 1 plays a critical role in the regulation of tumor development and/or progression, but its prognostic significance and relationship with Bcl-xL expression in ovarian carcinoma are unclear., Methodology/principal Findings: In the present study, the methods of Western blotting and immunohistochemistry (IHC) were utilized to investigate the expression status of Beclin 1 and Bcl-xL in fresh ovarian tissues and paraffin-embedded epithelial ovarian tumor tissues. Decreased expression of Beclin 1 was examined by IHC in 8.3% of normal ovaries, in 15.4% of cystadenomas, in 20.0% of borderline tumors, and in 55.6% of ovarian carcinomas, respectively. In ovarian carcinomas, decreased expression of Beclin 1 was correlated closely with ascending histological grade, later pT/pN/pM status and/or advanced clinical stage (P<0.05). In univariate survival analysis, a highly significant association between low-expressed Beclin 1 and shortened patient survival was evaluated in ovarian carcinoma patients (P<0.01), and Beclin 1 expression was an independent prognostic factor as evidenced by multivariate analysis (P = 0.013). In addition, decreased expression of Beclin 1 was inversely correlated with altered expression of Bcl-xL in ovarian carcinoma cohort, and combined analysis further showed that the low Beclin 1/high Bcl-xL group had the lowest survival rate., Conclusions/significance: Our findings suggest that Beclin 1 expression, as examined by IHC, could be served as an additional tool in identifying ovarian carcinoma patients at risk of tumor progression, and predicting patient survival in ovarian carcinomas with increased expression of Bcl-xL.

Pancreatic acinar cystadenomas (ACAs) are rare cystic lesions showing acinar differentiation with benign outcome. Although debated, ACAs are favored to be neoplastic and potentially the benign counterpart of acinar cystadenocarcinoma. We present the largest single institution series to date comprising 10 cases. The mean age was 49 years with a female predominance (M:F=1:2.3). Abdominal/flank pain was the most common presentation (n=6). Serum amylase/lipase and cyst fluid amylase were often elevated. All lesions had a benign outcome on follow-up (5 to 67 mo). The lesions were unilocular (n=3) or multilocular (n=7) with mean size of 3.8 cm (range, 2.9 to 5.0 cm) and 5.1 cm (range, 2.0 to 7.5 cm), respectively. Eight lesions were unifocal with locations as follows: head (n=2), head/neck (n=2), body (n=1), tail (n=1), predominantly extrapancreatic with a microscopic intrapancreatic component (n=1), and unspecified location (n=1). Two lesions were multifocal, involving the head/uncinate/body and pancreatic head, respectively. Two aspects of ACAs that may represent a diagnostic pitfall include the propensity for acinar epithelium to appear as nondescript flat/cuboidal epithelium (trypsin/chymotrypsin immunopositive) and epithelial heterogeneity, with focal mucinous and squamous epithelium, the latter particularly in multilocular variants. In addition, 2 cases with intracystic nodules were observed. Array comparative genomic hybridization performed on 1 of these cases showed multiple chromosomal gains involving 1p, 3p, 5q, 6p, 7q, 8, 10q, 11, 14, 20, and X. These findings provide preliminary evidence that ACAs represent a cystic neoplastic lesion.

XIAP-associated factor 1 (XAF1) was identified as a novel X-linked inhibitor of apoptosis (XIAP) binding partner that can reverse the anti-apoptotic effect of XIAP. XAF1 levels are greatly decreased in many cancer tissues and cell lines. The aim of this study was to investigate the expression of XAF1 and XIAP in advanced epithelial ovarian cancer and role of XAF1 in cisplatin resistance of ovarian cancer cells. Tissues from 94 patients with advanced epithelial ovarian cancer (EOC) and 30 ovarian cystadenomas were obtained. We analyzed the association of the immunohistochemical-determined expression of these two factors and clinicopathologic variables, overall survival, and angiogenesis. We established SKOV3 cells stably overexpressing XAF1 and explored the possible functions of XAF1 in ovarian cancer cells in vitro and in vivo. The protein expression of XAF1 was significantly lower and that of XIAP higher in malignant than nonmalignant tissues. Low XAF1 expression was associated with high-grade tumors and poor overall survival for patients. XAF1 expression was associated with microvessel density. Overexpression of XAF1 suppressed cell proliferation and enhanced SKOV3 cells sensitivity to cisplatin, as well as inhibited tumor growth and decreased MVD in vivo. Overexpression of XAF1 induced XIAP inactivation, caspase-3 activation and cytosolic expression of cytochrome c. These results suggested that XAF1 may be involved in ovarian cancer development and up-regulation of XAF1 may confer sensitivity of ovarian cancer cells to cisplatin-mediated apoptosis., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Aberrant nuclear factor-erythroid 2 (NRF2) expression correlates with tumor development. We investigated NRF2 expression in ovarian epithelial carcinoma (OEC), aiming to identify associations with clinicopathological factors, hormones and induced reactive oxygen species (ROS). Immunohistochemical staining for NRF2 expression was performed on 10 benign cystadenomas, 4 boderline tumors and 64 OECs. Western blotting was used to determine the effects of hormones on NRF2 expression in OEC. NRF2 protein was found to be overexpressed in OEC. Gonadotrophins and estrogen induced ROS production in OEC; these hormones also enhanced NRF2 expression. Therefore, aberrant expression may be induced by hormones through ROS signaling. Increased NRF2 expression may be a molecular event in OEC carcinogenesis.

In this report, we describe a case of hitherto unreported primary retroperitoneal acinar cell cystadenoma that morphologically and immunophenotypically resembled pancreatic acinar cell cystadenoma. Pancreatic acinar cell cystadenoma is a very uncommon benign lesion characterized by acinar cell differentiation, the evidence of pancreatic exocrine enzyme production, and the absence of cellular atypia. Our case occurred in a 55-year-old woman presenting a 10-cm multilocular cystic lesion in the retroperitoneum thought to be a mucinous cystic neoplasm. At laparotomy, the cystic mass, which showed no connection with any organ, was completely resected with a clinical diagnosis of cystic lymphangioma. The diagnosis of retroperitoneal acinar cell cystadenoma was based on the recognition of morphological acinar differentiation, the immunohistochemical demonstration of the acinar marker trypsin, and the absence of cellular atypia. These peculiar features can be used in the differential diagnosis with all the other cystic lesions of the retroperitoneum., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Oncocytic cystadenoma is a rare benign tumor of major salivary glands that in rare occasions may present histologically with intraluminal crystalloids. We report a case of 53-year-old man with a progressively enlarging lump in the left submandibular region. Ultrasound examination revealed a cystic mass with an intraluminal fluid collection. The tumor was surgically removed. Histologic examination yielded a diagnosis of oncocytic cystadenoma with a high concentration of intraluminal crystalloids. The microscopic features of the crystalloids were compatible with nontyrosine (alpha-amylase) crystalloids. When compared with previously published cases in the literature, this is the first report of oncocytic cystadenoma with intraluminal crystalloids arising in the submandibular gland, and the second reported case of the nontyrosine type of crystalloids occurring in association with this tumor. The nontyrosine crystalloids may be highly characteristic to salivary gland tumors with oncocytic differentiation.

Objective: Although human chemokinelike factor (CKLF)-like MAL and related proteins for vesicle trafficking transmembrane, domain-containing member 5 (CMTM5) has been proved to play an important role in carcinogenesis and apoptosis in several types of human tumors, the expression of CMTM5 in ovarian cancer remains unclear. We aimed to investigate the association between CMTM5 expression and the survival of patients with epithelial ovarian cancer., Methods: Normal surface ovarian epithelium tissues, ovarian cystadenoma tissues, ovarian cancer tissues, and 5 ovarian cancer cell lines were collected. The CMTM5 expressions were determined by reverse transcription polymerase chain reaction, Western blotting, and immunohistochemical staining. The survival information was analyzed by the Kaplan-Meier method., Results: The CMTM5 expression was down-regulated in ovarian cancers. The expression of CMTM5 was absent in 30% (24 of 80) of ovarian cancers compared with 4.55% (1 of 22) of normal surface ovarian epithelium tissues and ovarian cystadenomas by immunohistochemistry. The results from the reverse transcription polymerase chain reaction were consistent with those from Western blotting. Furthermore, we found that although CMTM5 expression has no significant correlation with the age of the patients (P = 0.342), clinical stages (P = 0.155), pathologic types (P = 0.0605), or status of metastasis (P = 0.554), it was associated with the 3 groups of different differentiation levels (P = 0.0026) and an increase of CMTM5 loss of expression ratio in patients with preoperative CA125 level more than 500 mIU/mL compared to those with less than 500 mIU/mL (48.57% vs 16.67%, P = 0.0130). Statistical analysis by the Kaplan-Meier method showed that CMTM5 expression had no significant impact on the prognosis of patients with ovarian cancer (P = 0.24)., Conclusions: The reduced expression of CMTM5 correlates significantly with poorly differentiated ovarian cancer and high preoperative CA125 level. CMTM5 may contribute to the pathogenesis of human epithelial ovarian cancer.

Background: No previous reports on the variation in the histopathological patterns of well-differentiated sebaceous carcinoma are yet to be published., Methods: We reviewed the histopathology of six examples of well-differentiated extraocular sebaceous carcinoma., Results: Two distinct histopathological patterns of sebaceous carcinoma, namely a secretory pattern (N = 2) and a non-secretory pattern (N = 4), were defined. The secretory pattern is typified by sebaceous lobular architecture with focal holocrine secretion, whereas the non-secretory pattern lacks this organoid quality. Both carcinomas with the secretory pattern showed low-grade cytological atypia, whereas the four carcinomas with the non-secretory pattern included three lesions with high-grade cytological atypia. A sebaceous adenoma-like area was seen in both secretory pattern carcinomas, whereas a focus of intraepithelial sebaceous carcinoma (sebaceous carcinoma in situ) was seen in two of the non-secretory pattern carcinomas., Conclusions: The clinicopathological significance of the two histopathological patterns remains unclear, because the number of reported cases is limited. It is possible that these two histopathological patterns of carcinoma have different histogenetic and prognostic implications, but no definitive conclusions can be made until further studies of a larger number of cases can be completed., (Copyright © 2011 John Wiley & Sons A/S.)

YKL-40 is a glycoprotein secreted by numerous human cells, such as cartilage, synovial, and endothelial cells. The biological role of YKL-40 has not yet been fully unveiled, however, its participation is perceived in angiogenesis, growth, proliferation, differentiation, and remodeling processes. The primary goal of our study was to evaluate possible differences in tissue immunoexpression of YKL-40, assumed between high grade and low-grade ovarian cancers and between the above-mentioned cancer types and benign lesions. Another purpose was to find out whether immunoexpression of the studied protein could correlate with the tumor proliferation process, evaluated by Ki-67 immunoexpression. The analysis comprised 45 women, diagnosed and treated for epithelial ovarian tumors at the Medical University of Lodz between 1997 and 2002. YKL-40 protein immunoexpression was semiquantitatively assessed, whereas immunoexpression of Ki-67 was evaluated using a computer image analysis system. Significantly higher immunoexpression values of both examined proteins were observed in high-grade serous ovarian cancers vs. low-grade and benign tumors. Moreover, a significant positive correlation was identified between the immunoexpressions of YKL-40 and Ki-67 proteins in the studied groups of tumors. In conclusion, the obtained data suggest an overt prominence of TKL-40 tissue immunoexpression of YKL-40 in high-grade serous ovarian tumors, which could then be approached as a helpful, additional marker to identify more aggressive ovarian cancers., (Copyright © 2011. Published by Elsevier GmbH.)

The 1st pediatric case of sertoliform cystadenoma with unique features is described herein. The patient is a 6-year-old boy who presented with gynecomastia and a left testicular cystic mass. Histopathologically the tumor was found to originate from the rete channels, filling and distending them with areas of mural Sertoli cell proliferations reminiscent of large cell Sertoli cell tumor (noncalcifying form) and showing widespread intratubular Sertoli cell proliferation islands in the vicinity. Histopathologic and immunohistochemical features are described in light of the relevant literature.

Survivin is a unique member of the inhibitor of apoptosis (IAP) protein family. As abnormal inhibition of apoptosis during homeostasis is considered a critical step in the initiation of cancer, we investigated prognostic value of survivin expression in epithelial ovarian carcinomas. We carried out immunohistochemical experiments using a polyclonal antisurvivin antibody to stain formalin-fixed paraffin-embedded sections from 91 patients with ovarian tumors, including 10 cystadenomas, 17 borderline tumors, and 64 epithelial ovarian carcinomas. Nuclear and cytoplasmic survivin staining was scored separately. Survivin expression was undetectable in ovarian cystadenomas and was weakly detected in 4 of 17 (23.53%) borderline tumors. In contrast, nuclear and cytoplasmic survivin staining was observed in 55 of 64 (85.94%) epithelial ovarian carcinomas. Scoring on the basis of the percentage of survivin nuclear-positive cells indicated that nuclear survivin expression was associated significantly with clinical stage, histologic grade, proliferating cell nuclear antigen (PCNA)-labeling index, and clinical outcome in ovarian epithelial carcinoma patients (P<0.01). Taken together, the results of this study provide evidence that nuclear survivin expression is a strong, independent prognostic marker for poor clinical outcomes in epithelial ovarian carcinoma.

Ovarian cancer, one of the most common gynecological malignancies, has an aggressive phenotype. It is necessary to develop novel and more effective treatment strategies against advanced disease. Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways involved in tumorigenesis, and represent potential targets for anticancer therapies. In this study, we performed cDNA subtraction following polymerase chain reaction (PCR) using degenerate oligonucleotide primers to identify specifically overexpressed PTKs in ovarian cancer. Three PTKs, janus kinase 1, insulin-like growth factor 1 receptor, and discoidin domain receptor 1 (DDR1), were identified and only DDR1 was overexpressed in all ovarian cancer tissues examined for the validation by quantitative real-time PCR. The DDR1 protein was expressed in 63% (42/67) of serous ovarian cancer tissue, whereas it was undetectable in normal ovarian surface epithelium. DDR1 was expressed significantly more frequently in high-grade (79%) and advanced stage (77%) tumors compared to low-grade (50%) and early stage (43%) tumors. The expression of the DDR1 protein significantly correlated with poor disease-free survival. Although its functional role and clinical utility remain to be examined in future studies, our results suggest that the expression of DDR1 may serve as both a potential biomarker and a molecular target for advanced ovarian cancer.

Objective: The purpose of this study was to evaluate the immunohistochemical Rb2/p130 expression in a series of benign, borderline, and malignant ovarian tumors., Study Design: Seventy-six operative specimens were analyzed. Frequencies and percents were calculated for variables by each of the 5 disease stage groups in increasing severity and again for the disease stage groups collapsed into benign (serous cystadenoma or endosalpingosis), low-grade [serous borderline tumors (SBT) or low-grade serous carcinoma (LGSC)] and high-grade serous carcinoma., Results: There was no loss of expression in benign serous cystadenomas (0/18). Ten percent of SBT's (2/20), 47% of LGSC's (9/19), and 16% of HGSC's (3/16) had loss of expression. There was a significant difference in the expression during the progression from cystadenoma to SBT to LGSC., Conclusions: Loss of Rb2/p130 expression is a rare event in benign cystadenoma. The progression to LGSC is associated with a decrease in gene expression.

Background: Octamer-4 (Oct4) is a well known regulator of self-renewal in embryonic stem cells; it has been detected in several human cancers and may play a critical role in carcinogenesis., Aims: To assess the expression of Oct4 in epithelial ovarian tumours., Methods: Expression of Oct4 was evaluated by immunohistochemistry in 460 cases of various epithelial ovarian lesions as well as 35 cases of normal fallopian tube epithelium. The association between Oct4 expression and various clinical pathological parameters was analysed., Results: Oct4 expression was significantly increased from normal epithelium (both ovarian epithelium and fallopian tube epithelium) to benign and borderline cystadenoma to carcinoma in the serous lesion subgroup. Oct4 overexpression was associated with more advanced FIGO stage and higher histological grade in serous adenocarcinoma. Conversely, Oct4 expression did not differ among mucinous lesions or correlate with clinicopathological parameters in patients with mucinous adenocarcinoma., Conclusion: Results suggest that Oct4 expression may contribute to the initiation, promotion and progression of serous ovarian carcinoma; it might be a useful biomarker for the diagnosis and outcome prediction of serous ovarian carcinoma.

An unusual case of ovarian adenosarcoma arising from a smooth-walled serous cystadenoma is described. The ovary was replaced by a multiloculated, fluid-filled cyst without any solid or papillary areas. The malignant component was underdiagnosed during frozen section examination as benign cystadenoma because of the deceptively benign gross appearance of the tumor. On the permanent sections, a phyllodes-like pattern of stromal proliferation and periglandular condensation of atypical stromal cells with a mitotic count of 3 per 10 high-power fields was more apparent and led to the diagnosis of adenosarcoma. The malignant component could not be distinguished from the benign component using immunohistochemical analysis. To our knowledge, this is the first reported case of an adenosarcoma arising from a grossly benign cystadenoma and the third case in the literature of an adenosarcoma associated with a cystadeno(fibro)ma. This case also shows the challenges in differentiating adenosarcoma from a benign counterpart on both frozen and permanent sections.

Background: Laminopathies are a group of rare genetic disorders characterized by multiple-tissue degeneration. We describe a new laminopathy with ovarian cystadenoma and explore its molecular etiology., Methods: The case is a 15-year-old girl who presents the prominent progeroid disorders, multiple system degeneration and early-onset cystadenoma of the ovary. Candidate genes including LMNA, ZMPSTE24, PPAR G, INSR and WRN were sequenced to screen for DNA variants. The mRNA and protein expression levels of LMNA were examined in primary fibroblasts. The pathophysiological events such as morphologic alterations, cell senescence, cell proliferation, apoptosis and pRb as well as p53 protein expressions were also investigated in primary fibroblasts., Results: No mutation was identified in the candidate genes screened. Nuclear abnormalities including nuclear blebs, mislocalization of lamin A/C were evident in the patient fibroblasts. Ultrastructurally, nucleus exhibited nuclear herniation and almost complete loss of peripheral heterochromatin. In addition, lamin C protein expression was markedly reduced whereas lamin A protein level was normal and no prelamin A was detected in the primary fibroblasts. Although the senescence-associated beta-galactosidase staining of patient' cells was negative, cells in S phase increased in accompany with a decrease in pRb protein expression. Furthermore, increases in apoptotic cell death and p53 expression were observed., Conclusions: Our data suggest that selective deficiency of lamin C protein is associated with a case of laminopathy with ovarian cystadenoma. The abnormalities in nuclear structure and alterations in gene expression such as the decrease in pRb and increase in p53 may be responsible for the multiple tissue degeneration.

Multilocular prostatic cystadenoma is a rare benign neoplasm located between the bladder and the rectum. These are prostatic tissue and have been shown to harbor high-grade intraepithelial neoplasia and likely susceptible to the same disease processes seen in the prostate gland. We report the first case of conventional prostatic adenocarcinoma involving a multilocular cystadenoma. Distinction from cystadenocarcinoma is also made.

Objective: ATP-binding Cassette (ABC) transporters are thought to cause multiple drug resistance (MDR) in various carcinomas. Gene expression data from individual transporters in ovarian cancer tissue is contradictory and also scarce for some of them. RNA levels of a panel of ABC transporters were collected and analyzed to get a more detailed overview which transporters are of importance in resistance to chemotherapeutic agents in ovarian carcinoma., Methods: Real-time PCR was used to determine RNA expression levels of 9 ABC transporters in 50 benign tissue samples and 50 recurrent ovarian cancer samples. Genes exhibiting a significant difference between those two groups were further evaluated in 50 primary cancer samples. Data were analyzed with receiver operating characteristic (ROC) curves and multiple Wilcoxon-Mann-Whitney U-tests with Shaffer correction., Results: Gene expression of four transporters (ABCC1, ABCC2, ABCC3, and ABCB3) was significantly elevated in recurrent cancer lesions compared to benign tissue. Expression levels of these 4 ABC transporters were further analyzed in primary ovarian cancer lesions. A significant difference between primary and recurrent tumor tissue was found in all four genes. Changes in gene expression between benign samples and primary lesions were minor and not relevant., Conclusions: Four of the examined ABC transporters are likely to play a role in the MDR of ovarian carcinoma. Gene expression of these transporters seems only up regulated through chemotherapy. The thesis that MDR in ovarian cancer is acquired through therapy itself and not present ab initio is supported by these findings., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Inactivating mutations of the tumor suppressor gene TSC2 are associated with tumorigenesis in tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis. Statins, as 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, have the potential to limit the growth of these tumors by limiting the isoprenylation of activated GTPases in Tsc2-null cells. We tested atorvastatin as a therapy for (a) ethylnitrosourea (ENU)-enhanced renal cystadenoma and (b) spontaneous liver hemangioma in 129Sv/Jae Tsc2(+/-) mice. ENU-treated Tsc2(+/-) mice were given atorvastatin chow (0.1%, w/w) for 1 or 3 months before sacrifice at 6 months; 129Sv/Jae Tsc2(+/-) mice were given atorvastatin chow (0.1%, w/w) for 6 months before sacrifice at 12 months. All treatment groups were compared with mice of identical genotype and strain background that were fed control chow. Pathologic analyses revealed a predominance of renal cystadenoma in ENU-treated and liver hemangioma in non-ENU-treated 129Sv/Jae Tsc2(+/-) mice. In both cohorts, serum cholesterol levels and levels of phosphorylated S6 and GTP-RhoA in healthy tissue were significantly (>50%) reduced in atorvastatin-treated mice as compared with controls. Following atorvastatin treatment, no significant reduction in tumor size, morphology, or phosphorylated S6 levels was observed for either ENU-associated renal cystadenoma or spontaneous liver hemangioma as compared with the untreated groups. In conclusion, although the marked reduction in cholesterol levels indicates that atorvastatin was effective as an 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, it did not inhibit the growth of tumors that develop in these Tsc2(+/-) models, suggesting that it is unlikely to have benefit as a single-agent therapy for TSC-associated tumors.

Objectives: Our previous study has suggested an oncogenic role of eIF-5A2 in ovarian tumorigenesis. Abnormalities of eIF-5A2 and its clinical/prognostic significance, however, in ovarian carcinoma are unclear., Methods: In this study, we examined expression of EIF-5A2, using immunohistochemistry, in 30 normal ovaries, 30 ovarian cystadenomas, 30 borderline ovarian tumors and 110 ovarian carcinomas. The amplification status of eIF-5A2 in each ovarian carcinoma was assessed by fluorescence in situ hybridization., Results: Overexpression of EIF-5A2 was detected in none of the normal ovaries, 7% cystadenomas, 30% borderline tumors, and 53% invasive ovarian carcinomas, respectively. Amplification of eIF-5A2 was detected in 16% of informative ovarian carcinomas. In ovarian carcinomas, significant positive associations were found between overexpression of EIF-5A2 and the tumors ascending grade, later pT/pN and FIGO stages, as well as increased positive rate of Ki-67 (p<0.05). In univariate survival analysis of the ovarian carcinoma cohorts, a significant association of overexpression of EIF-5A2 with shortened patient survival (mean 39.0 months vs 69.5 months, p<0.001) was demonstrated. Importantly, EIF-5A2 expression provided significant independent prognostic parameters in multivariate analysis (p=0.043)., Conclusions: These findings suggest that increased expression of EIF-5A2 in ovarian carcinoma may represent an acquired malignant phenotypic feature of tumor cells, and the overexpression of EIF-5A2, as detected by immunohistochemistry, is an independent molecular marker for shortened survival time of patients with ovarian carcinoma.

Cystic tumor lesions of the pancreas are relatively uncommon. Advances in imaging and pathohistology, including immunohistochemistry, have led to the detection and classification of novel tumor entities. A promoting aspect is the extended indication profile in pancreatic surgery, in particular, because of lower perioperative morbidity and mortality. One of these classified cystic neoplasms of the pancreas is serous oligocystic adenoma (SOIA), a rare and benign tumor lesion. We report on a 41-year-old man with a cystic lesion within the pancreatic head. Therefore, he underwent pylorus-preserving cephal duodenopancreatectomy. Pathohistologic investigation revealed a SOIA. He had a medical history significant for subtotal colectomy because of a synchronous double colonic carcinoma. Both tumor tissue specimens had been characterized for a high level of microsatellite instability (MSI) and loss of hMLH1, as well as for a corresponding germ line mutation in hMLH1 gene, leading to the diagnosis of hereditary non-polyposis associated colon cancer (HNPCC). The case is remarkable since the SOIA revealed MSI and loss of hMLH1 protein in the tumor cells that has never been reported for this tumor type. In addition, there is a rare and extraordinary association between SOIA and HNPCC, which has never been published before, since SOIA, in this case, could have been developed in the setting of HNPCC syndrome.

Background: Dual expression of potential biomarkers in both benign and malignant pancreatic tumors was a major obstacle in the development of diagnostic biomarkers of early pancreatic cancer., Methods: To better understand the limitations of potential protein biomarkers in pancreatic cancer, we employed two-dimensional difference gel electrophoresis technology and tandem mass spectrometry to study protein expression profiles in pancreatic cancer tissues, benign pancreatic adenoma and normal adjacent pancreas. Seven differently expressed proteins were selected for validation by Western blot and/or immunohistochemistry., Results: 21 spots were overexpressed and 24 spots were downexpressed in pancreatic cancer compared with benign and normal adjacent tissues. Our study demonstrated that three candidate pancreatic ductal adenocarcinoma biomarkers identified in previous studies, fructose-bisphosphate aldolase A, alpha-smooth muscle actin and vimentin, were also overexpressed in pancreatic cystadenoma, which might lower their further utility as biomarkers for pancreatic cancer. Aflatoxin B(1) aldehyde reductase (AKR7A2) was confirmed to be only highly expressed in pancreatic cancer, not in normal adjacent pancreas and benign tumors., Conclusions: The protein profile pattern of pancreatic cystadenoma was more similar to normal adjacent pancreas than pancreatic cancer. We identified panels of the upregulated proteins in pancreatic cancer, which have not been reported in prior proteomic studies. AKR7A2 may be a novel potential biomarker for pancreatic cancer., (Copyright 2008 S. Karger AG, Basel and IAP.)

Salivary gland cystadenomas are cystic neoplasms with diverse architecture and cytology. Cystadenomas may have a considerable intracystic epithelial component, but an epithelial proliferation in small ducts and cysts resembling atypical ductal hyperplasia of breast has not been documented. The patient was a 68-year-old man with a slow growing right submandibular mass. He has no recurrence 13 months after resection. The tumor was polycystic and measured 3.0 x 2.5 x 2.5 cm. The epithelium of the larger cysts was composed of flat, cuboidal, columnar, and apocrine-like cells. Many of the larger cysts showed "Roman bridges", epithelial tufting, and papillae. The smaller cysts and ducts had apocrine-like cells forming secondary glandular lumens. The ductal cells were surrounded by clear myoepithelial cells. Nuclear pleomorphism and hyperchromasia was seen in the apocrine-like cells. Adjacent to the larger cysts, there was an adenomatoid proliferation of small ducts surrounded by myoepithelial cells. No mitotic activity, necrosis, or stromal invasion was identified. The ductal cells were diffusely positive for keratin 7 and androgen receptors with focal expression of keratin 19 and high-molecular weight keratin. S-100, estrogen and progesterone receptors, and BRST-2 were negative in the ductal cells. Recognition of a prominent intraductal epithelial component in cystadenomas is important to avoid a misdiagnosis of cystadenocarcinoma or low-grade salivary duct carcinoma. Cystadenomas join the list of salivary gland lesions with microscopic similarities to primary lesions of the breast.

An imbalance between pro-angiogenic and anti-angiogenic factors is hypothesized in the pathogenesis of ovarian cystic disease. The aim of the following study was to explore the possible role of free vascular endothelial growth factor receptor 1 (sVEGFR-1), a soluble regulator of vascular endothelial growth factor (VEGF) action, in ovarian cystoadenoma, endometriomata and cystoadenocarcinoma. Forty-eight women, of whom fourteen had ovarian serous cysts, twenty-eight had stage III-IV ovarian endometriomata, and six had stage IIIB-IIIC ovarian carcinoma, were included. Sampling of serum, peritoneal and ovarian cystic fluids and of tumor tissue was performed before, during and following surgery, respectively. Levels of VEGF and sVEGFR-1 were measured in serum, peritoneal and cystic fluid. VEGF and sVEGFR-1 expression was evaluated in tumor tissue. There were no differences in serum VEGF and sVEGFR-1 levels nor in VEGF/VEGFR-1 ratio between study groups. Peritoneal fluid VEGF levels were higher in cystoadenocarcinoma patients than in endometriosis and in cystoadenoma patients, while sVEGFR-1 peritoneal fluid concentrations were significantly higher only in endometriosis-affected women. VEGF/VEGFR-1 ratio was highest in the peritoneal fluid of cancer patients with respect to the other two groups of women. Cystic fluid VEGF and VEGFR-1 concentrations were higher in endometriomata and in cystoadenocarcinomas than in cystadenomas but the VEGF/VEGFR-1 ratio was highest in cancer patients. Western blot evidenced a marked expression of VEGF and soluble VEGFR-1 in endometriosis tissue with respect to benign cyst tissue but a lower expression of both molecules, contrary to that expected, in cancer tissue. In conclusion, all in all, our data indicate that an excess of local VEGF with respect to its soluble receptor VEGFR-1 may be a key factor in the onset and maintenance of pathological neo-angiogenesis in ovarian cyst formation.

A novel class of putative progestin binding proteins has been recently identified as potential mediators of rapid nongenomic hormone actions. The proteins designated membrane progestin receptor (mPR) alpha, beta, and gamma were initially discovered in fish and shown to have a role in oocyte maturation. The predicted multiple membrane spanning domain structure of the mPRs resembles that of heptahelical G-protein-coupled receptors. Phylogenetic analysis indicated that the mPRs belong to the large progestin and adiponectin Q receptor (PAQR) gene family. Based on the reported expression of the 3 mPRs in hormone-responsive tissues of the female reproductive tract and on the role of steroid hormones in cancer, we investigated the expression of these novel progestin receptors in epithelial tumors of the ovary. The transcript levels of the 3 human mPR/PAQRs were assessed by semiquantitative reverse transcriptase polymerase chain reaction in 28 ovarian samples, including normal tissues, cystadenomas, borderline tumors, and common types of ovarian carcinomas. Two of the 3 transcripts for the mPR/PAQRs proteins appeared differentially expressed in the tumors examined. Expression of mPR alpha and beta was demonstrated in ovarian tumors at both messenger RNA and protein level, and their expression appeared to be independent of the expression of the classic nuclear progestin receptors. Expression of mPR gamma (PAQR V) was elevated in endometrioid and clear cell carcinomas, 2 related neoplastic counterparts of hormonally responsive tissues, suggesting a potential role of the mPR/PAQRs in the pathogenesis of epithelial ovarian tumors.

We compared immunohistochemical expression of hepatocyte growth factor (HGF), c-met, alpha-inhibin, estrogen receptor (ER), and progesterone receptor (PR) in 10 pancreatic mucinous cystic neoplasms (PMCNs), 8 hepatobiliary cystadenomas (HBCs), and 6 simple liver cysts (SLCs).All HBCs and PMCNs were in women (mean ages, 45.7 and 54.9 years, respectively; P > .05). All HBCs had abundant stroma; PMCN stromal density was more variable (score, 3.0 vs 1.8; P < .05). Stroma in HBCs had greater ER and PR staining (both P < .05) and more consistent, focal, strong reactivity for alpha-inhibin than PMCNs (P < .05). SLCs were found in men and women, lacked ovarian-type stroma, and were negative for ER, PR, and alpha-inhibin. HGF expression was not significantly different in the epithelium of HBCs, PMCNs, and SLCs; c-met expression in the epithelium of HBCs and PMCNs was significantly stronger than in SLCs (P < .05). Differences in stromal density and ER, PR, and alpha-inhibin immunoreactivity in HBCs and PMCNs suggest that different hormonal environments in the liver and pancreas contribute to stromal variation. Up-regulation of c-met in HBCs and PMCNs suggests c-met activation in the pathogenesis of pancreaticobiliary cystic neoplasms.

Purpose of Investigation: Significant progress has been made in recent years in the understanding of the mechanisms postulated by the gonadotropin theory of ovarian carcinogenesis. In the present study we compare FSH concentrations between serum and fluid from cysts or the rectouterine pouch of patients with epithelial tumors and non-neoplastic lesions., Methods: We enrolled 277 patients. They were divided into five groups: I (n = 44)--ovarian cancer patients, II (n = 16)--borderline tumors, III (n = 40)--benign epithelial cystadenomas, IV (n = 137)--non-neoplastic lesions and V (n = 22)--admitted for "second-look" laparoscopy., Results: There were any significant differences between FSH concentrations in serum and tumor fluid in patients with ovarian cancer (36.46 vs 28.11 mIU/ml) and borderline epithelial tumors (31.5 vs 22.7 mIU/ml). For benign cystadenomas the respective concentrations were 28.96 mIU/ml in serum and 6.93 mIU/ml in tumor fluid in these groups p < 0.0000001. The same highly significant differences were found in non-neoplastic lesions (24.97 vs 4.77 mIU/ml), p < 0.0000001. Patients who underwent "second-look" laparoscopy demonstrated significant differences (p < 0.05) as FSH concentration in serum and peritoneal fluid when neoplastic cells were not disclosed, but the difference was not significant (p = 0.752) when fluid from the rectouterine pouch was positive for carcinoma cells., Conclusions: The results of our study can reflect an ineffective tumor: blood barrier and easy diffusion of gonadotropins into the tumor tissue. Local reduction of FSH levels through administration of GnRH analogs may in some clinical situations produce clear therapeutic benefits for the management of ovarian malignancies.

An 82-year-old postmenopausal woman presented with severe clinical hyperandrogenism related to testosterone overproduction, possibly as a result of a mucinous cystadenoma. The cystadenoma was successfully removed in toto. The patient was discharged in good health. Plasma testosterone levels normalised 6 weeks after surgery. Ovarian mucinous cystadenomas are a rare cause ofhyperandrogenism.

The occurrence of an atypical fibroxanthoma in association with a syringocystadenoma papilliferum is reported. Both neoplasms showed characteristic histologic features and displayed typical immunohistochemical profiles. The neoplasms developed in intimate admixture in an area of nevus sebaceus.

To further characterize the immunohistochemical features of hepatobiliary cystadenoma with mesenchymal stroma, a battery of stains was performed on nine typical cases. All nine tumors had been resected from female patients who ranged in age from 30 to 59 years. Freshly cut sections were stained with antibodies to estrogen receptor (ER), progesterone receptor (PR), alpha-smooth muscle actin (SMA), inhibin-alpha, and cytokeratins (CK) 7, 8, 18, and 19. Nuclear staining of the mesenchymal stromal cells for ER and PR was present in all and seven out of nine cases, respectively. A strong cytoplasmic staining of the mesenchymal stromal cells for SMA was seen in all cases. A patchy pale cytoplasmic staining of the tumor epithelium for ER and PR was seen in five out of nine and four out of nine cases, respectively. Immunoreactivity of luteinized stromal cell for inhibin-alpha was documented in three out of nine cases. All tumors (nine out of nine) demonstrated strong cytoplasmic positivity of the epithelial lining of the cysts to CK7, CK8, CK18, and CK19, typical of biliary-type epithelium. The expression of ER, PR, and inhibin-alpha in the ovarian-like stroma supports the likely hormonal dependence of this tumor and probably explains its almost exclusive occurrence in women.

Aim: To study the gene expression changes in pancreatic cystic neoplasm in SV40Tag transgenic mice model and to provide information about the prevention, clinical diagnosis and therapy of pancreatic cancer., Methods: Using the pBC-SV40Tag transgenic mice model of pancreatic cystic neoplasm, we studied the gene expression changes by applying high-density microarrays. Validation of part gene expression profiling data was performed using real-time PCR., Results: By using high-density oligonucleotide microarray, of 14113 genes, 453 were increased and 760 decreased in pancreatic cystic neoplasm, including oncogenes, cell-cycle-related genes, signal transduction-related genes, skeleton-related genes and metabolism-related genes. Among these, we confirmed the changes in Igf, Shh and Wnt signal pathways with real-time PCR. The results of real-time PCR showed similar expression changes in gene chip., Conclusion: all the altered expression genes are associated with cell cycle, DNA damage and repair, signal pathway, and metabolism. SV40Tag may cooperate with several proteins in promoting tumorigenesis.

Aim: To recognize cystic neoplasia of the pancreas and thus to identify a panel of curable diseases., Methods: Sixty-four cases of cystic neoplasia of the pancreas, including 28 cases of intraductal papillary mucinous neoplasia (IPMN), 12 cases of serous cystic neoplasia (SCN), 11 cases of mucinous cystic neoplasia (MCN), 11 cases of solid pseudo-papillary neoplasia (SPN), and 2 cases of solid tumor with cystic degeneration were examined immunohistochemically for their expression of MUC1, MUC2, MUC4, MUC5AC, and MUC6, as well as other related antigens., Results: Adenoma type of IPMN and borderline lesions exhibited high expressions of MUC2, and MUC5AC. In contrast, IPMN with invasive carcinoma component showed MUC1 immunoreactivity. SCN was mainly positive for MUC1 and MUC6, while negative for MUC2, MUC4 and MUC5AC. Noninvasive MCN, regardless of its cellular atypia degree, was positive for MUC5AC and negative for MUC1. MUC1 expression was only observed in patients with an invasive component. No mucin expression was found in SPN., Conclusion: Mucin profile may, in conjunction with histologic study, provide important information on tumor types and patient treatment of cystic neoplasia of the pancreas.

Biliary cystic tumors, which are also called biliary cystadenoma and cystadenocarcinoma, are thought to be a heterogeneous disease entity, and some of them are known to show a luminal communication to the bile duct. In this study, we examined the clinicopathological features of nine cases of biliary cystic tumors with bile duct communication. They were composed of five males and four females with an average age of 67 years (52-84 years). They were multilocular (eight cases) or unilocular (one case), and all cases contained mucinous fluid. A direct luminal communication with the bile ducts was identified in five cases on preoperative or intraoperative cholangiographies. Biliary cystic tumors examined in this study were histologically adenoma (one case), adenocarcinoma in situ (six cases), and adenocarcinoma associated with microinvasive mucinous carcinoma (two cases). One case of adenocarcinoma in situ also had the adenoma component (adenocarcinoma in adenoma). Dysplastic mucinous epithelium proliferated in flat, micropapillary and papillary fashions within the intracystic spaces. Intraepithelial neoplasm was observed within non-dilated adjacent bile ducts, suggesting a direct luminal communication between the cystic tumors and the bile duct. Ovarian-like stroma was not observed in their walls in any cases. Immunohistochemically, seven cases expressed MUC1 or MUC2 in the neoplastic biliary epithelium. All cases except one were alive without any evidences of tumor recurrence after total excision (3-156 months after surgery). These clinicopathological features resembled those of intraductal papillary neoplasm of the bile duct, which had been reported as a biliary counterpart of pancreatic intraductal papillary mucinous neoplasm. In conclusion, biliary cystic tumors with bile duct communication could be regarded as intraductal papillary neoplasm with a prominent cystic dilatation of the bile duct and mucin retention, rather than true biliary cystic neoplasms., (Published online 2 June 2006.)

To clarify the features of apocrine mixed tumors (AMT) of the skin among benign neoplasms with apocrine differentiation in their relationship to follicular stem cells, we investigated the immunohistochemical expression of CK15 (LHK15 and C8/144B), which is a relatively specific marker of hair follicle stem cells in the bulge, in 35 cases of eight different benign neoplasms with presumed apocrine differentiation. All eight cases of AMT of the skin showed CK15 immunostaining of the neoplastic cells, and all four cases of syringocystadenoma papilliferum, all five cases of spiradenoma, and both cases of cylindroma also showed a focally positive reaction to CK15. None of the other benign neoplasms with presumed apocrine differentiation showed CK15 expression. In AMT of the skin, the proportion of CK15-positive cells in the follicular or sebaceous differentiation group (78.8%, average of four cases) was significantly higher than the group without this differentiation (8.8%, average of four cases). AMT of the skin are unique among benign neoplasms with apocrine differentiation in their substantial and constant CK15 expression, suggesting that they derive from multipotent epithelial stem cells in the bulge. AMT of the skin with follicular or sebaceous differentiation are considered to show an immature stage of apocrine differentiation still rich in stem cells or to originate from stem cells with an incompletely established apocrine fate. The partially positive reaction for CK15 in syringocystadenomas papilliferum and spiradenoma/cylindroma may depend on the ability to express CK15 in stem cells with an apocrine fate or result from the follicular and apocrine nature of this neoplasm.

Background: When ovarian carcinoma is diagnosed in stage I, up to 90% of patients can be cured with surgery and currently available chemotherapy. At present, less than 25% of cases are diagnosed at this stage. To increase the fraction of ovarian cancers detected at an early stage, screening strategies have been devised that utilize a rising serum CA125 level to trigger the performance of transvaginal sonography. One limitation of CA125 as an initial step in such a screening strategy is that up to 20% of ovarian cancers lack expression of the antigen. Serum tumor markers that can be detected in ovarian cancers that lack CA125 expression might improve the sensitivity for early detection., Methods: From 296 ovarian cancers, 65 (22%) were found to have weak or absent CA125 expression on immunoperoxidase staining. Tissue expression of CA125 was compared to serum CA125 levels. Using immunoperoxidase staining of tissue arrays, we have assessed expression of 10 potential serum tumor markers in the 65 epithelial ovarian cancers with little or no CA125 expression and in ovarian cystadenomas, tumors of low malignant potential, normal ovaries, and 16 other normal tissues., Results: Low or absent expression of CA125 in surgical specimens of epithelial ovarian cancer was associated with low levels of serum CA125 in pre-operative serum specimens. In ovarian cancers that lacked CA125, all specimens (100%) expressed human kallikrein 10 (HK10), human kallikrein 6 (HK6), osteopontin (OPN), and claudin 3. A smaller fraction of CA125-deficient ovarian cancers expressed DF3 (95%), vascular endothelial growth factor (VEGF) (81%), MUC1 (62%), mesothelin (MES) (34%), HE4 (32%), and CA19-9 (29%). When reactivity with normal tissues was considered, however, MES and HE4 showed the greatest specificity. Differential expression was also found for HK10, OPN, DF3, and MUC1., Conclusions: At the level of tissue expression, each of 10 potential serum markers could be detected in 29-100% of ovarian cancers that had low or absent expression of CA125. Several markers exhibited more intense expression in cancers than in normal organs. Further investigation is needed to demonstrate complementary expression of markers in serum.

Aim: To compare the clinico-pathological features of intraductal papillary mucinous cystic tumours (IPMT) and mucinous cystic tumours (MCT) of the pancreas., Methods: Eighteen patients with IPMT and 18 with MCT who underwent surgical resection between 1990 and 2004 were retrospectively reviewed. Their clinico-pathological features were compared using univariate analysis. Statistical analyses of potential predictive factors of malignancy for each of these two groups were also conducted., Results: Patients with IPMT were found to be older (64+/-10 vs 43+/-18 years, p<0.001) and were predominantly male (male:female ratio, 5:4 vs 1:17, p=0.003) as compared to patients with MCT. MCTs were found in the body-tail region (100%) whereas IPMTs were more evenly distributed (50% in the head) (p=0.001). Pathologically, IPMT was distinct from MCT in terms of size (3.8+/-3.2 vs 9.1+/-4.4 cm, p=0.001), association with secondary pancreatitis (50 vs 0%, p=0.011), communication with the pancreatic duct (94 vs 0%, p<0.001), presence of a dilated main pancreatic duct (61 vs 0%, p<0.001) and the presence of ovarian-type stroma (0 vs 44%, p=0.003)., Conclusion: IPMT and MCT are distinct clinico-pathological entities. This distinction is important as management and outcome of these entities may differ.