Search

Solid pseudopapillary neoplasms of the pancreas are rare neoplasms that have been shown to harbor recurrent somatic pathogenic variants in the beta-catenin gene, CTNNB1. Here, we used targeted next generation sequencing to analyze these tumors for other associated mutations. Six cases of solid pseudopapillary neoplasms were studied. DNA extracted from formalin-fixed paraffin embedded tissue blocks was analyzed using the Ion Torrent platform, with the 50-gene Ampliseq Cancer Hotspot Panel v2 (CHPv2), with further variant validation performed by Sanger sequencing. Four tumors (67%) were confirmed to harbor mutations within CTNNB1, two with c.109T > G p.(Ser37Ala) and two with c.94G > A p.(Asp32Asn). One case showed a frameshift deletion in the Adenomatous Polyposis Coli gene, APC c.3964delG p.(Glu1322Lysfs*93) with a variant allele frequency of 42.6%. Sanger sequencing on non-tumoral tissue confirmed the variant was somatic. The patient with the APC mutation developed metastasis and died. In addition to the four cases harboring CTNNB1 variants, we found a case characterized by poor outcome, showing a rare frameshift deletion in the APC gene. Since the APC product interacts with beta-catenin, APC variants may, in addition to CTNNB1, contribute to the pathogenesis of solid pseudopapillary neoplasms via the Wnt signaling pathway.

ObjectiveThis study aimed to determine the frequency of malignant pathology in a macroscopically normal appendix during surgery for a borderline or malignant mucinous ovarian tumor (MOT).MethodsWomen with borderline and malignant MOT were identified from the pathology database from 2000 to 2014. Women who had a benign MOT and had an appendicectomy were excluded from the study. Data were collected from the electronic patient record and case notes.ResultsOf 310 women identified with MOT, 203 patients with benign MOT were excluded. Of the remaining 107 patients, 15 patients with previous appendicectomy were also excluded. The study population consisted of 92 patients. There were 57 (62%) patients with borderline MOT and 35 (38%) patients with malignant MOT. In the borderline subgroup, 40/57 (70%) patients had appendicectomy of whom 8 (20%) had macroscopically abnormal appendices. One patient had pseudomyxoma peritonei secondarily involving the appendix and 7 patients had a histologically normal appendix. Normal histology was found in all macroscopically normal appendices. In the malignant subgroup, 29/35 (83%) patients had an appendicectomy. There were 8 (27.5%) macroscopically abnormal appendices with a malignant pathology in 7 (87.5%) patients and 1 patient had a resolving appendicitis. There were 21 macroscopically normal appendices of which, serrated adenoma was found in 1 (4.8%) patient, whereas the remaining 20 (95.2%) patients had normal histology.ConclusionsIn MOT, an abnormal appearing appendix should be excised. If the appendix is grossly normal, our data do not support performing an appendicectomy as part of a surgical staging procedure.

Solid pseudopapillary neoplasms of the pancreas are rare neoplasms that have been shown to harbor recurrent somatic pathogenic variants in the beta-catenin gene, CTNNB1. Here, we used targeted next generation sequencing to analyze these tumors for other associated mutations. Six cases of solid pseudopapillary neoplasms were studied. DNA extracted from formalin-fixed paraffin embedded tissue blocks was analyzed using the Ion Torrent platform, with the 50-gene Ampliseq Cancer Hotspot Panel v2 (CHPv2), with further variant validation performed by Sanger sequencing. Four tumors (67%) were confirmed to harbor mutations within CTNNB1, two with c.109T G p.(Ser37Ala) and two with c.94G A p.(Asp32Asn). One case showed a frameshift deletion in the Adenomatous Polyposis Coli gene, APC c.3964delG p.(Glu1322Lysfs*93) with a variant allele frequency of 42.6%. Sanger sequencing on non-tumoral tissue confirmed the variant was somatic. The patient with the APC mutation developed metastasis and died. In addition to the four cases harboring CTNNB1 variants, we found a case characterized by poor outcome, showing a rare frameshift deletion in the APC gene. Since the APC product interacts with beta-catenin, APC variants may, in addition to CTNNB1, contribute to the pathogenesis of solid pseudopapillary neoplasms via the Wnt signaling pathway.

Mesonephric adenocarcinoma (MA) of the vagina is an extremely rare tumour of the female genital tract. There are currently 22 reported cases in the published literature. Consequently, its pathophysiology and disease progression remain poorly understood. A 63-year-old woman presented with a history of a swelling in her vagina. Two-dimensional pelvic floor ultrasound and MRI demonstrated a multiloculated cyst with no malignant features. Initial workup provided a working diagnosis of a suburethral cyst. The diagnosis of MA was made on histology after excision of the cyst. Subsequent postoperative investigation showed no spread of the disease. The patient completed a course of prophylactic brachytherapy to prevent the possibility of any recurrence of disease. Due to its rarity, it remains difficult to diagnose MA of the vagina even on histological analysis. We would therefore recommend a low threshold to excise or perform tissue biopsy of unspecified vaginal masses.

Clear cell sarcoma–like tumor of the gastrointestinal tract (CCSLGT) is a rare malignant neoplasm that occurs in the wall of the small bowel, stomach, or large bowel, predominantly in young adults. It is an aggressive neoplasm that frequently presents with metastatic disease and has a high mortality rate. Histologically, it is usually composed of medium-sized primitive ovoid or epithelioid cells with pale or clear cytoplasm that are arranged in sheets or in papillary or alveolar architectures. Clear cell sarcoma–like tumor of the gastrointestinal tract is positive for S100 protein, invariably negative for melanocyte-specific markers and is often also positive for neuroendocrine markers. The etiology of CCSLGT is unknown, but many studies have shown associations with EWSR1-CREB1 gene fusions and, less frequently, with EWSR1-ATF1 fusions. Here, we discuss the current status of CCSLGT, including histologic, immunophenotypic, and molecular findings.

Although myelolipomas of the adrenal glands are detected with increasing frequency with advances in imaging, the occurrence of myelolipoma with adrenal cortical carcinoma remains very rare. We present a case of combined myelolipoma with adrenal cortical carcinoma in a 47-year-old man. In previously reported cases of adrenal cortical carcinoma and myelolipoma, the latter occurred as incidental foci within or peripheral to the carcinoma, perhaps representing “myelolipomatous metaplasia” rather than true neoplasia. We describe a new finding, in which the myelolipomatous component consisted of a large mass adjacent and dominant to the carcinoma. The presence of these 2 defined and apparently independent tumors suggests, in this case, the occurrence of collision or synchronous neoplastic events, rather than of metaplasia.

Ovarian mucinous tumors (OMTs) of the intestinal type share morphologic features with primary tumors of other sites, and it can often be difficult to distinguish primary ovarian from metastatic mucinous tumors. MUC1, MUC2, MUC5AC, and MUC6 expressions were studied by immunohistochemistry in 36 OMTs of intestinal type (17 malignant, 19 borderline), 18 pancreatic, 12 biliary, 15 esophageal, 9 gastric, and 7 colorectal/appendiceal adenocarcinomas. All samples were from primary sites, except for colorectal tumors which were from ovarian metastases. Borderline and malignant OMTs show similar mucin immunoprofile, being strongly and uniformly positive for MUC5AC (97.2% of cases), whereas only focally positive for MUC1 (19.4%), MUC2 (38.9%), and MUC6 (22.2%). The positive frequencies of pancreatic adenocarcinomas for MUC1, MUC2, MUC5AC, and MUC6, respectively, were 100%, 16.7%, 94.4%, and 61.1%; for biliary (cholangiocarcinomas) were 91.7%, 0%, 16.7%, and 8.3%; for esophageal carcinomas were 73.3%, 33.3%, 53.3%, and 26.7%; for gastric carcinomas were 44.4%, 44.4%, 44.4%, and 0% and for lower gastrointestinal tract cancers were 28.6%, 85.7%, 42.9%, and 0%. Our study shows that OMTs are usually MUC5AC+/MUC1-, which is different from pancreatic, biliary, esophageal, gastric, and colorectal/appendiceal carcinomas. We recommend that these mucin stains be added to the panel of immunostains to differentiate metastatic tumors to the ovary from primary OMTs.

Introduction. Soft tissue tumour pathology is a highly specialised area of surgical pathology, but soft tissue neoplasms can occur at virtually all sites and are therefore encountered by a wide population of surgical pathologists. Potential sarcomas require referral to specialist centres for review by pathologists who see a large number of soft tissue lesions and where appropriate ancillary investigations can be performed. We have previously assessed the types of diagnostic discrepancies between referring and final diagnosis for soft tissue lesions referred to our tertiary centre. We now reaudit this 6 years later, assessing changes in discrepancy patterns, particularly in relation to the now widespread use of ancillary molecular diagnostic techniques which were not prevalent in our original study.Materials and Methods. We compared the sarcoma unit's histopathology reports with referring reports on 348 specimens from 286 patients with suspected or proven soft tissue tumours in a one-year period.Results. Diagnostic agreement was seen in 250 cases (71.8%), with 57 (16.4%) major and 41 (11.8%) minor discrepancies. There were 23 cases of benign/malignant discrepancies (23.5% of all discrepancies). 50 ancillary molecular tests were performed, 33 for aiding diagnosis and 17 mutational analyses for gastrointestinal stromal tumour to guide therapy. Findings from ancillary techniques contributed to 3 major and 4 minor discrepancies. While the results were broadly similar to those of the previous study, there was an increase in frequency of major discrepancies.Conclusion. Six years following our previous study and notably now in an era of widespread ancillary molecular diagnosis, the overall discrepancy rate between referral and tertiary centre diagnosis remains similar, but there is an increase in frequency of major discrepancies likely to alter patient management. A possible reason for the increase in major discrepancies is the increasing lack of exposure to soft tissue cases in nonspecialist centres in a time of subspecialisation. The findings support the national guidelines in which all suspected soft tissue tumour pathology specimens should be referred to a specialist sarcoma unit.

Intra-abdominal cysts have a variety of origins, of which lymphatic and mesothelial types are the most commonly encountered. Here we describe a combined mesothelial cyst and lymphangioma arising within the small bowel subserosa of an 80-year-old woman. This was found incidentally at laparotomy performed for an unrelated condition. To date, such a hybrid lesion has not been previously reported. The ways by which this lesion might have arisen are discussed.

Primaryde novoangiosarcoma of the breast is an uncommon, aggressive neoplasm. Here, we present a case of a young woman who initially developed primary angiosarcoma of the breast, and subsequently angiosarcoma of the ovary during pregnancy two years later. Only two confirmed primary angiosarcomas of the breast metastasizing specifically to the ovary have been described in the literature. However, all previous cases had ovarian metastases at presentation or shortly after initial diagnosis. This case is unusual as it occurred after a relatively long interval, and apparently developed during pregnancy. We discuss this rare phenomenon, as well as the possible factors contributing to the recurrence.

PURPOSE: The expression of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) is associated with poor prognosis in sporadic colorectal carcinoma (CRC). EGFR inhibitors are approved for the treatment of refractory CRC. The aim of this study was to investigate the expression of EGFR and HER2 and downstream extracellular signal regulated kinase (ERK) and mitogen activated protein kinase (MAPK) in non-neoplastic colonic mucosa, adenomas and carcinomas from familial adenomatous polyposis coli (FAP) patients, exploring the expression along the adenoma-carcinoma sequence. METHODS: The expression of EGFR, HER2, phosphorylated MAPK/ERK kinase (pMEK) and phosphorylated ERK (pERK) proteins was studied by immunohistochemistry in samples of colonic non-neoplastic mucosa (n = 65), adenomas (n = 149) and adenocarcinomas (n = 16) from each of the 16 FAP patients. RESULTS: For HER2, only weak cytoplasmic expression was seen in 8% of adenomas, 6% of carcinomas and 3% of the non-neoplastic mucosa. EGFR was expressed in non-neoplastic mucosa, adenomas and carcinomas with a statistically significant increase in expression in adenomas compared with non-neoplastic mucosa (p

While endometriosis, defined as the presence of endometrial tissue in extrauterine sites, is most frequently encountered within the peritoneal cavity, a small but significant proportion of cases occur at extra-abdominal soft tissue sites, particularly in relation to previous abdominal surgery. We reviewed the cases of endometriosis of soft tissue sites seen at a tertiary soft tissue center. All cases of extra-abdominal soft tissue endometriosis diagnosed at this institution over a 13-year period were reviewed, and clinical and pathologic findings were recorded. Forty-five patients had diagnoses of soft tissue endometriosis and there were 34 diagnostic biopsies and 26 surgical excision specimens. All but 1 case were abdominal wall lesions, with 1 located in the upper arm. A total of 33 patients presented with lesions in scars of previous operations (31 in Pfannenstiel incisions for Caesarean sections, presenting with a median interval of 6 years (range 1-16 years) following surgery). The lesions ranged in size from 1 to 8 cm (median 3.5 cm). One case showed decidualized stroma with trophoblast cells, while 2 had secondary adenocarcinoma arising from endometriosis. Eighteen cases were tested for β-catenin expression immunohistochemically, of which 5 showed at least focal nuclear positivity in the surrounding fibrous tissue (although not within glands or stroma). Soft tissue endometriosis is seen most commonly in surgical scars, particularly following Caesarean sections. Spontaneous endometriosis also most commonly occurs in the abdominal wall, although can occur exceptionally at unusual sites, such as extremities. Secondary changes, including carcinomas, can arise from endometriosis. The differential diagnosis of these lesions includes fibromatosis, which may be erroneously diagnosed on small, nonrepresentative core biopsy specimens.

Background Inflammatory mediators influence tumour progression. IL-8 has been shown to have pro-angiogenic, mitogenic and motogenic effects and several studies have demonstrated the expression of IL-8 by various human pancreatic cancer cell lines. Methods: The expression of IL-8 and IL-8 receptors was studied in 52 pancreatic adenocarcinomas and 52 pancreatic neuroendocrine tumours using immunohistochemistry. The expression of IL-8 and IL-8 receptors was also assessed in eight pancreatic adenocarcinomas and seven neuroendocrine tumours in comparison to normal pancreatic tissue using real time quantitative PCR (qRT-PCR). Results: Immunohistochemical analysis of the expression of IL-8, IL-8RA and IL-8RB in 52 pancreatic adenocarcinomas demonstrated expression in 25%, 75% and 79% of pancreatic adenocarcinomas, respectively. There was no statistically significant correlation between expression and tumour grade and stage for any of the three antigens. IL-8, IL-8RA and IL-8RB expression was detected in 21%, 63% and 92% of 52 pancreatic neuroendocrine tumours. There was no statistically significant correlation between expression and tumour grade for any of the three antigens. Using qRT-PCR, the expression of each of IL-8, IL-8RA and IL-8RB mRNA was increased in 75% of pancreatic adenocarcinomas. IL-8, IL-8RA and IL-8RB mRNA expression was also increased in 57%, 43% and 29% of pancreatic neuroendocrine tumours. Quantitatively, there was a significant increase in expression level of IL-8 in tumours of both types in comparison to normal pancreatic tissue (38.5-fold in adenocarcinomas and 43.9-fold in neuroendocrine tumours). There was also increased expression of IL-8RA in both tumour types, with higher levels in adenocarcinomas, 2.7-fold and neuroendocrine tumours, 1.7-fold. IL-8RB was slightly increased in adenocarcinomas in comparison to normal pancreas (1.4-fold), but the expression was decreased in neuroendocrine tumours compared with normal pancreas (0.9-fold). Conclusion: This is the first study to show that IL-8 and IL-8 receptors are upregulated in both pancreatic adenocarcinomas and neuroendocrine tumours, and indicate this signalling pathway may modulate tumour behaviour through autocrine and/or paracrine loops.

Fulvestrant is a pure estrogen receptor (ER) antagonist with no agonist effects. We describe the experience of a single center involving 45 postmenopausal women with advanced breast cancer where fulvestrant was utilized following progression on tamoxifen and a third generation aromatase inhibitor. Patients received fulvestrant as first line one (2%), second line 18 (40%), third line 13 (29%), fourth line 10 (22%), and fifth line three (7%) treatment. Median duration of treatment with Fulvestrant was 4 months (range 1-20 months). One patient had a partial response, 14 other (31%) experienced clinical benefit (CB) (defined as response or stable disease for at least 6 months). The median time to progression (TTP) from initiation of fulvestrant was 4 months (range 1-20 months) and the median survival was 10 months (range 1-55 months). In those patients who experienced CB the median TTP was 10 months (range 6-20) and median survival was 21 months (range 7-55). Fulvestrant was well tolerated; two patients experienced side effects severe enough to stop therapy. Despite the fact that fulvestrant was used in the majority of cases, later in the treatment sequence CB was seen in a number of patients. This data suggest fulvestrant is well tolerated and is a useful treatment option in patients with advanced breast cancer who progress on prior endocrine treatment.

Objectives: To evaluate the efficacy and toxicity of paclitaxel and cisplatin alternating with paclitaxel and etoposide doublet regimen (TP/TE), for salvage of patients with high-risk gestational trophoblastic neoplasia (GTN).Patients and methods: Twenty-four patients with GTN received TP/TE. Sixteen had failed previous chemotherapy including six with cisplatin-based regimens (group A) and eight changed to TP/TE because of prior treatment-induced toxic effects (group B).Results: In group A, three patients (19%) achieved a complete response (CR) and five (31%) a partial response (PR). All CR and four PR patients remain alive with a median follow-up of 25 months (range 9-48). The eight patients failing TP/TE subsequently died. Thus, the overall survival of the 16 patients in group A was 44% (seven of 16), rising to 70% (seven of 10) if the six patients who had failed prior cisplatin-based chemotherapy were excluded. In group B, four patients were assessable for response (two CR, two PR) and six remain alive (median follow-up 19 months) giving an overall survival of 75%. TP/TE was well tolerated, with only one patient discontinuing therapy because of toxic effects.Conclusion: TP/TE is an effective, well-tolerated, salvage treatment for relapsed patients who are heavily pretreated for GTN. Further studies of this regimen are warranted.

AimsSoft tissue tumours are a heterogeneous group of neoplasms that can arise at almost every anatomical site. As they often show similar clinical and radiological findings, histology is the definitive diagnostic method and it is crucial that the surgical pathology report contains accurate, useful information for management and prognostication. The soft tissue sarcoma minimum dataset produced by the Royal College of Pathologists in the UK outlines a structure for handling and reporting soft tissue tumours, including the core data required, and aiding pathologists in forming a consistent reporting approach.MethodsWe assessed the information in surgical pathology reports for soft tissue lesions at a tertiary soft tissue centre, in 1 year prior to the development of this dataset, and 1 year after its release, to audit the comparative adequacy of macroscopic and microscopic information provided, and to assess for differences in reporting since the advent of routine ancillary molecular diagnostic testing.Results and conclusionsWe found that while essential information was always included in reports, more specific details contributing to better quality reports such as more detailed macroscopic descriptions and a higher proportion of clinical summaries with radiological correlation were included in 2011 than 2006, despite increasing workload. Specimen handling, particularly of core biopsies, was also improved, reflecting the increasing need to conserve the maximum amount of patient material for molecular investigations.

Primary fibrosarcoma arising from ovarian sex-cord stroma is a very rare neoplasm, with only a few reports in the literature. These tumors have been reported to express inhibin which allows their distinction from fibrosarcomas of soft tissue. Here, we report a case of a fibrosarcoma arising in the broad ligament. Despite being totally separate from the ovary, the tumor was diagnosed as sex-cord stromal type on the basis of inhibin expression. Furthermore, this patient suffered a recurrence of her tumor in the pelvis, which showed both the fibrosarcomatous, as well as other sex-cord elements, confirming the sex-cord stromal differentiation of the sarcoma. To our knowledge, this is the first case of a sex-cord stromal fibrosarcoma arising from an extraovarian site. Furthermore, this is also the first case of a recurrent fibrosarcoma, which showed redifferentiation of the tumor into other sex-cord components.

Fluorescence in situ hybridization (FISH) for FOXO1 gene rearrangement and reverse transcription-polymerase chain reaction (PCR) for PAX3/7-FOXO1 fusion transcripts have become routine ancillary tools for the diagnosis of alveolar rhabdomyosarcomas (ARMS). Here we summarize our experience of these adjunct diagnostic modalities at a tertiary center, presenting the largest comparative series of FISH and PCR for suspected or possible ARMS to date. All suspected or possible ARMS tested by FISH or PCR for FOXO1 rearrangement or PAX3/7-FOXO1 fusion transcripts over a 7-year period were included. FISH and PCR results were correlated with clinical and histologic findings. One hundred samples from 95 patients had FISH and/or PCR performed. FISH had higher rates of technical success (96.8 %) compared with PCR (88 %). Where both tests were utilized successfully, there was high concordance rate between them (94.9 %). In 24 histologic ARMS tested for FISH or PCR, 83.3 % were translocation-positive (all for PAX3-FOXO1 by PCR) and included 3 histologic solid variants. In 76 cases where ARMS was excluded, there were 3 potential false-positive cases with FISH but none with PCR. PCR had similar sensitivity (85.7 %) and better specificity (100 %) in aiding the diagnosis of ARMS, compared with FISH (85 and 95.8 %, respectively). All solid variant ARMS harbored FOXO1 gene rearrangements and PAX3-FOXO1 ARMS were detected to the exclusion of PAX7-FOXO1. In comparative analysis, both FISH and PCR are useful in aiding the diagnosis of ARMS and excluding its sarcomatous mimics. FISH is more reliable technically but has less specificity than PCR. In cases where ARMS is in the differential diagnosis, it is optimal to perform both PCR and FISH: both have similar sensitivities for detecting ARMS, but FISH may confirm or exclude cases that are technically unsuccessful with PCR, while PCR can detect specific fusion transcripts that may be useful prognostically.

Background. The assessment ofMDM2gene amplification by fluorescencein situhybridization (FISH) has become a routine ancillary tool for diagnosing atypical lipomatous tumor (ALT)/well-differentiated liposarcoma and dedifferentiated liposarcoma (WDL/DDL) in specialist sarcoma units. We describe our experience of its utility at our tertiary institute.Methods. All routine histology samples in whichMDM2amplification was assessed with FISH over a 2-year period were included, and FISH results were correlated with clinical and histologic findings.Results. 365 samples from 347 patients had FISH forMDM2gene amplification. 170 were positive (i.e., showedMDM2gene amplification), 192 were negative, and 3 were technically unsatisfactory. There were 122 histologically benign cases showing a histology:FISH concordance rate of 92.6%, 142 WDL/DDL (concordance 96.5%), and 34 cases histologically equivocal for WDL (concordance 50%). Of 64 spindle cell/pleomorphic neoplasms (in which DDL was a differential diagnosis), 21.9% showedMDM2amplification. Of the cases with discrepant histology and FISH, all but 3 had diagnoses amended following FISH results. For discrepancies of benign histology but positive FISH, lesions were on average larger, more frequently in “classical” (intra-abdominal or inguinal) sites for WDL/DDL and more frequently core biopsies. Discrepancies of malignant histology but negative FISH were smaller, less frequently in “classical” sites but again more frequently core biopsies.Conclusions. FISH has a high correlation rate with histology for cases with firm histologic diagnoses of lipoma or WDL/DDL. It is a useful ancillary diagnostic tool in histologically equivocal cases, particularly in WDL lacking significant histologic atypia or DDL without corresponding WDL component, especially in larger tumors, those from intra-abdominal or inguinal sites or core biopsies. There is a significant group of well-differentiated adipocytic neoplasms which are difficult to diagnose on morphology alone, in which FISH forMDM2amplification is diagnostically contributory.

Aims Mucins (MUCs) constitute a family of glycoproteins expressed by epithelial cells. They show specific tissue-type expression, and are useful for differentiating between different cancers. Studies have shown changes in MUC expression with tumour progression in a variety of cancers. The aim of this study was to characterize the profile of MUC expression in benign, borderline and malignant intestinal-type ovarian mucinous tumours (OMTs). Methods and results MUC1, MUC2, MUC5AC and MUC6 expression was studied by immunohistochemistry in 53 OMTs (19 malignant, 25 borderline, and nine benign). The positivity frequencies of MUC1 in benign, borderline and malignant OMTs were 22.2%, 12%, and 31.6%, respectively. For MUC2, they were 0%, 40%, and 42.1%, respectively. For MUC5AC, they were 100%, 100%, and 94.8%, respectively. For MUC6, they were 66.7%, 16%, and 26.3%, respectively. Significantly increased MUC2 expression and decreased MUC6 expression were seen in borderline and malignant OMTs, as compared with benign tumours. Conclusion This is the first study to compare the expression of all four MUCs in OMT with statistical analysis. We show that MUC2 expression and MUC6 expression change with the progression of benign to borderline and malignant tumours. We suggest that these changes may contribute to malignant transformation.

A patient with leptomeningeal metastases from transitional cell bladder cancer is presented. As chemotherapy extends survival in patients with bladder cancer, the importance of sanctuary sites need

Background: Angiogenesis plays a key role in the progression of various tumors, including endometrial carcinomas. Several cytokines and their associated receptors are shown to be involved, particularly VEGF-A with VEGFR1, -2 and -3. Methods: The expressions of VEGF-A, VEGFR2 and VEGFR3 were studied in by immunohistochemistry in 76 endometrial carcinoma specimens. VEGFR2 and VEGFR3 receptor expression were also studied by qRT-PCR in 17 tumors in comparison to normal endometrium. The expression profiles were correlated with tumor type, grade, stage, lymphovascular invasion, disease free survival, and the expressions of other cytokine receptors (EGFR, CXCR1 and CXCR2). Results: Immunohistochemically, 63% of endometrial cancers expressed VEGF-A, 55% VEGFR2 and 26% VEGFR3. VEGFR3 was significantly correlated with tumor stage (p = 0.02), with a trend towards poorer disease free survival (p = 0.09). VEGF-A was significantly correlated with microvessel density (p

Introduction. Familial adenomatous polyposis (FAP) patients have a germline mutation in the adenomatous polyposis coli (APC) gene. The APC protein interacts with beta-catenin, resulting in the activation of the Wnt signalling pathway. This results in alterations in cell proliferation and apoptosis. We investigated the expression of beta-catenin and related proliferation and apoptotic factors in FAP patients, exploring the expression along the adenoma-carcinoma sequence.Methods. The expression of beta-catenin, p53, bcl-2, cyclin-D1, caspase-3, CD10, and Ki-67 proteins was studied by immunohistochemistry in samples of colonic nonneoplastic mucosa (n=71), adenomas (n=152), and adenocarcinomas (n=19) from each of the16 FAP patients.Results. The expression of beta-catenin, caspase-3, cyclin-D1, and Ki-67 was increased in both adenomas and carcinomas in FAP patients, compared with normal mucosa. p53 and CD10 expression was only slightly increased in adenomas, but more frequently expressed in carcinomas. Bcl-2 expression was increased in adenomas, but decreased in carcinomas.Conclusion. This is the first study investigating collectively the expression of these molecules together in nonneoplastic mucosa, adenomas, and carcinomas from FAP patients. We find that beta-catenin and related proliferative and apoptotic factors (cyclin-D1, bcl-2, caspase-3, and Ki-67) are expressed early in the sequence, in adenomas. However, p53 and CD10 are often expressed later in the sequence, in carcinomas.

Nicastrin (NCT) is a crucial component of the γ-secretase (GS) enzyme, which prompted investigations into its biological role in cancer. We have previously shown that nicastrin is overexpressed in breast cancer (BC), conferring worse overall survival in invasive, ERα negative patients. Here, we used 2D and 3D Matrigel, anchorage-independent growth conditions and a breast cancer xenograft mouse model to assess the impact of nicastrin on breast cancer stem cell (BCSC) propagation and invasion in vitro and tumor growth in vivo. Stable knockdown of nicastrin in HCC1806 breast cancer cells reduced cell invasion by 51.4 ± 1.7%, accompanied by a morphological change to a rounded cell phenotype and down-regulation of vimentin, Snail, Twist, MMP2, and MMP9. We observed a reduction of the pool of CD44 + /CD24 − and ALDH1 high breast cancer stem cells by threefold and twofold, respectively, and a reduction by 2.6-fold of the mammospheres formation. Nicastrin overexpression in nontransformed MCF10A cells caused an induction of epithelial to mesenchymal regulators, as well as a fivefold increased ALDH1 activity, a threefold enrichment for CD44 + /CD24 − stem cells, and a 3.2-fold enhanced mammosphere-forming capacity. Using the γ-sescretase inhibiton, Notch1/4 siRNA, and Akt inhibition, we show that nicastrin regulates breast cancer stem cells partly through Notch1 and the Akt pathway. Exploiting serial dilution transplantation of the HCC1806 cells expressing nicastrin and HCC1806 stably depleted of nicastrin, in vivo, we demonstrate that nicastrin inhibition may be relevant for the reduced tumorigenicity of breast cancer cells. These data could serve as a benchmark for development of nicastrin-targeted therapies in breast cancer.

Nicastrin is an essential component of the gamma secretase (GS) enzyme complex, required for its synthesis and recognition of substrates for proteolytic cleavage. The purpose of this study was to investigate whether nicastrin has prognostic value or potential as a therapeutic target in breast cancer (BC). The suitability of nicastrin as a target in BC was assessed using BC tissue microarrays (TMAs) (n = 1050), and its biological role in vitro was evaluated in BC cell lines following gene silencing. Nicastrin blocking antibodies were developed and evaluated for their suitability as potential clinical therapeutics. TMA and cell line analysis confirmed that nicastrin expression was upregulated in BC compared to normal breast cells. In TMA patient samples, high nicastrin expression was observed in 47.5% of cases and correlated with ERα expression, patient age, and tumor grade. In pre-defined subset analysis, high nicastrin expression predicted for worse BC specific survival in the ERα -ve cohort. In vitro gene silencing of nicastrin resulted in disruption of the GS complex and a decrease in notch1 cleavage. This was sufficient to increase E-cadherin expression and its co-localization with p120 catenin at cell-cell junctions in MCF7 cells. Nicastrin silencing in invasive MDA-MB-231 cells resulted in loss of vimentin expression and a marked reduction in both cell motility and invasion; which was concomitant with the de novo formation of cell-cell junctions characterized by the colocalization of p120 catenin and F-actin. These data indicate that nicastrin can function to maintain epithelial to mesenchymal transition during BC progression. Anti-nicastrin polyclonal and monoclonal antibodies were able to decrease notch1 and vimentin expression and reduced the invasive capacity of BC cells in vitro. This supports our hypothesis that a nicastrin blocking antibody could be used to limit metastatic dissemination in invasive BC.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas present more commonly in the elderly. This report describes a case of IPMN in a 36-year-old man who presented with obstructive jaundice and weight loss. The initial investigation by computed tomography scan revealed a cystic lesion in the head of pancreas fistulating into the duodenum and the common bile duct (CBD). Subsequent endoscopic retrograde cholangiopancreatography revealed a low CBD stricture with proximal filling defects. Mucin was observed extruding from the biliary orifice following an endoscopic sphincterotomy. A classic Whipple’s pancreatoduodenectomy was performed to excise the lesion. A histological examination of the lesion confirmed the presence of a malignant IPMN of the pancreas complicated by pancreatobiliary and pancreatoduodenal fistulae.

Background: Cancer in individuals living with HIV and AIDS is a common source of morbidity and mortality, especially in the underdeveloped world. As antiretrovirals are distributed with greater equity across the globe, individuals with HIV and AIDS are living longer and developing malignancies, as opposed to other opportunistic infections. Objective: This article reviews the gender differences in studies of AIDS-associated cancers, examining factors related to transmission, treatment, and outcome. Methods: MEDLINE, PubMed, Ovid, conference proceedings, and abstract books were searched from 1983 onward for English-language publications and data on gender differences related to AIDS-associated cancers. Relevant trials were similarly reviewed. The search terms used were women or gender, cancer or tumor or malignancy, lymphoma or Kaposi, and HIV or AIDS. Results: We found that studies in established market economies have focused predominantly on men, although a wider view suggests that the rapidly growing rates of HIV infection among women should prompt specific oncologic challenges. Conclusion: Immunosuppression-induced malignancies in women, Kaposi sarcoma in particular, are likely to represent a global issue in the future. (Gend Med..

Background The use of combined positron emission tomography/computerised tomography (PET/CT) scanners in oncology has been shown to improve the staging of tumours and the detection of relapses. However, mis-registration errors are increasingly recognised to be a common pitfall of PET/CT studies. Case Presentation We report a patient with a germ cell tumour of the testis, who underwent a PET/CT scan to detect the site of relapse with a view to surgical removal. However, the PET/CT scan mislocalised the tumour site to be within the T2 vertebral body. A subsequent endoscopic ultrasound scan however showed the tumour to be anterior to the vertebral body, which was confirmed at surgery. Conclusion In this report, we highlight the artefactual mislocalisation errors which may occur with PET/CT imaging, and the need to review and verify these scans.

The promyelocytic leukemia (PML) protein is aggregated into nuclear bodies that are associated with diverse nuclear processes. Here, we report that the distance between a locus and its nearest PML body correlates with the transcriptional activity and gene density around the locus. Genes on the active X chromosome are more significantly associated with PML bodies than their silenced homologues on the inactive X chromosome. We also found that a histone-encoding gene cluster, which is transcribed only in S-phase, is more strongly associated with PML bodies in S-phase than in G0/G1 phase of the cell cycle. However, visualization of specific RNA transcripts for several genes showed that PML bodies were not themselves sites of transcription for these genes. Furthermore, knock-down of PML bodies by RNA interference did not preferentially change the expression of genes closely associated with PML bodies. We propose that PML bodies form in nuclear compartments of high transcriptional activity, but they do not directly regulate transcription of genes in these compartments.