Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma.

Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obtained from 38 patients with resectable EAC before and after 2 cycles of oxaliplatin-fluorouracil chemotherapy. Pre-treatment mRNA expression of 280 DNA repair (DNAR) genes was tested for association with histopathological regression at surgery, disease-free survival (DFS) and overall survival (OS). High expression of 13 DNA damage repair genes was associated with DFS less than one year (P < 0.05); expression of 11 DNAR genes were associated with worse OS (P < 0.05). From clinical associations with outcomes, two genes, ERCC1 and EME1, were identified as candidate biomarkers. In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively. In clinical samples from the clinical trial, pre-treatment XPF protein levels were associated with pathological response, and MUS81 protein was associated with 1-year DFS. XPF and MUS81 merit further validation in prospective clinical trials as biomarkers that may predict clinical response of EAC to oxaliplatin-based chemotherapy.

The Ueno method for substaging pT1 colorectal adenocarcinoma by depth and width measurement: an interobserver study.

AIM: Early pT1 polyp colorectal cancers (CRCs) present challenges for accurate pathology substaging. Haggitt and Kikuchi stages depend on polyp morphology and are often difficult to apply due to suboptimal orientation or fragmentation, or absence of the muscularis propria in polypectomy or submucosal resection specimens. European guidelines for quality assurance suggest using Ueno's more objective approach, using depth and width measurements beyond muscularis mucosae. We have investigated interobserver variation using Ueno's approach. METHOD: Ten consecutive pT1 polyp CRCs were identified and the slides assessed by six gastrointestinal pathologists for depth and width of invasion. A further 60 polyps were studied by a group of specialist and general pathologists. Agreement was assessed by analysis of variance. A polyp CRC is classified as high risk if it has a depth ≥ 2000 µm or a width ≥ 4000 µm and low risk with a depth < 2000 µm or a width < 4000 µm. Concordance for the dichotomized values was assessed using the kappa statistic. RESULTS: The intraclass correlation coefficient (ICC) for depth was 0.83 and for width 0.56 in the 10-polyp group. The ICC for the 60-polyp CRCs was 0.67 for depth and 0.37 for width. In both groups, when polyp CRCs are divided into high- and low-risk categories based on depth, there was substantial and moderate agreement (κ = 0.80 and 0.47) but only fair agreement when based on width (κ = 0.34 and 0.35). CONCLUSION: Ueno's method has the advantage of being independent of polyp morphology. Our study shows better concordance for depth measurement and reproducibility in nonfragmented specimens, with poorer agreement when based on width.

Impact of the consideration of serrated polyps to the interval of colonoscopic surveillance in the NHS Bowel Cancer Screening Programme.

AIM: Most international post polypectomy surveillance guidelines do not recommend surveillance for serrated polyps. In the present study the additional impact of serrated polyps on surveillance intervals from international adenoma surveillance guidelines was investigated. METHOD: Endoscopic and pathology records were audited of participants in the NHS Bowel Cancer Screening Programme (guaiac faecal occult blood test, gFOBT) in 2011. Surveillance intervals were calculated for current guidelines and also for serrated polyps based on previously described aggressive and conservative strategies. RESULTS: In total, 389 patients were included of whom 141 (36.2%) were high risk (advanced adenoma: adenoma ≥ 10 mm, villous elements, high grade dysplasia, or adenoma ≥ 3 in number) needing surveillance at ≤ 3 years. Thirty-three (8.5%) had significant serrated polyps, of whom 18 (4.6% of the total) had significant serrated lesions and simultaneous advanced adenoma or ≥ 3 adenomas. Adopting an aggressive surveillance strategy, the mean overall absolute additional proportion of all such patients in the surveillance group at 3 years or less was 4.0% (3.9% - 4.1%; 4.2% women; 3.8% men). These proportions varied according to endoscopist from 2.3% to 4.7%. For more conservative strategies the increase was only 1%. CONCLUSION: The impact of including serrated polyps in current guidelines would result in a small increase in surveillance intervals for FOBT based bowel cancer screening. About half of those who might need surveillance for serrated polyps would already receive surveillance for being in a high risk adenoma group.

An incidental enterocolic lymphocytic phlebitis pattern is seen commonly in the rectal stump of patients with diversion colitis superimposed on inflammatory bowel disease.

AIMS: Enterocolic lymphocytic phlebitis (ELP) is an uncommon cause of bowel pathology and most frequently results in ischaemia. It is characterised by an artery-sparing, venulocentric lymphoid infiltrate that causes a phlebitis and vascular compromise. Rare cases of ELP have been encountered with lymphocytic colitis in the absence of ischaemic bowel change. The present study examined the occurrence of ELP in the setting of diversion colitis and inflammatory bowel disease, as well as in random colectomy specimens. METHODS: The study cohort comprised the following: 26 completion proctectomy specimens for ulcerative colitis with superimposed diversion colitis in the rectal stump; 3 colectomy specimens for Crohn disease with diversion colitis; 6 colectomy specimens for adenocarcinoma and/or diverticular disease with diversion colitis; 34 resection specimens with ulcerative colitis only; 19 with Crohn disease only; and 100 random colon resection specimens for adenocarcinoma, adenoma, diverticular disease and ischaemia. RESULTS: ELP was present in 18 of the 26 ulcerative colitis cases with diversion colitis, 3/3 Crohn disease cases with diversion colitis, 1/6 cases of diverticular disease with diversion colitis, 6/34 cases of ulcerative colitis without diversion, 2/19 Crohn disease cases without diversion colitis, and only 1 of 100 colectomy cases without inflammatory bowel disease or diversion colitis. CONCLUSION: ELP occurs most frequently in cases that have been diverted for inflammatory bowel disease. Fewer cases of ELP were noted in cases of inflammatory bowel disease in the absence of diversion colitis. It is postulated that altered bowel flora and immune dysregulation may be pivotal in the causation of this association.

Revision 2: an immunohistochemical approach and evaluation of solid pseudopapillary tumour of the pancreas.

Solid pseudopapillary tumours (SPT) of the pancreas are uncommon, but with widespread and increased imaging, several of these lesions are coming to light incidentally and are subject to needle biopsies. On limited material and especially the solid or clear cell, variants of SPT can morphologically mimic most notably pancreatic neuroendocrine tumours and even metastatic renal cell carcinoma or melanoma. In this context, immunohistochemistry is important and useful in helping to reach the correct diagnosis. Several antibodies have been used in the immunohistochemical evaluation of SPT. As with most tumours, no one marker is specific, but rather a core panel is advocated. Recently, both beta-catenin and E-cadherin have been shown to be of value in SPT. Nuclear and cytoplasmic decoration of tumour cells by beta-catenin is seen in almost 100% of cases. This protein relocalisation away from the cell membrane is underscored by mutations of the beta-catenin gene. Mutations of the CDH1 gene are very uncommon in SPT, but the immunohistochemically detected changes to the protein are consistent and present in 100% of cases. Using an E-cadherin antibody to the extracellular domain of the molecule results in complete membrane loss, while the antibody directed to the cytoplasmic fragment produces distinct nuclear staining of the tumour cells. In addition, there is concordance of staining abnormalities between the two antibodies. When combined with CD10 and progesterone receptor positivity, a diagnosis of SPT can be rendered with confidence even in small biopsy samples.

MRI total sagittal abdominal diameter as a predictor of metabolic syndrome compared to visceral fat at L4-L5 level.

OBJECTIVE: To compare associations between anteroposterior (AP) diameter or sagittal abdominal diameter - a measure of total central fat, and visceral fat alone with the metabolic syndrome as defined by ATPIII criteria. RESEARCH DESIGN AND METHODS: Twenty-four Caucasian male with type 2 diabetes and 24 non-diabetic Caucasian male subjects [body mass index (BMI) (+/-SD): 32.23 +/- 7.52 kg/m(2), age (+/-SD): 51.35 +/- 13.80 years] were studied by magnetic resonance imaging (MRI) scan to measure central fat at L4-L5 level. The visceral and total central adipose tissue was calculated in cm(2) and total sagittal MRI diameter and visceral sagittal MRI diameters in cm. Components of the ATPIII definition of the metabolic syndrome and circulating adipocytokine concentrations were also measured. RESULTS: MRI total sagittal abdominal diameter was positively associated with waist circumference in controls (r=0.62, p=0.007) and in diabetic subjects (r=0.81, p<0.001). Binary logistic regression analysis showed that MRI-calculated total sagittal diameter (r=0.61, p=0.002) was a more significant predictor of the adverse metabolic profile of the metabolic syndrome than MRI-assessed visceral fat. Receiver operating characteristic curves revealed that MRI-calculated total sagittal diameter most effectively identified subjects with the metabolic syndrome. CONCLUSIONS: MRI-calculated total sagittal abdominal diameter is a non-validated MRI method that predicts the adverse metabolic profile of the ATPIII definition of the metabolic syndrome. Antero-posterior fat is a dimension of central fat that seems to be more closely associated with cardiovascular risk compared to visceral fat.

Membrane loss and aberrant nuclear localization of E-cadherin are consistent features of solid pseudopapillary tumour of the pancreas. An immunohistochemical study using two antibodies recognizing different domains of the E-cadherin molecule.

AIM: To examine the expression of E-cadherin in solid pseudopapillary tumours (SPT) of the pancreas using two monoclonal antibodies recognizing two different domains of the E-cadherin molecule. METHODS AND RESULTS: Twenty cases of SPT were collected and a tissue microarray (TMA) constructed. The TMA was stained with commercially available antibodies to E-cadherin and beta-catenin. All 20 cases displayed nuclear beta-catenin as well as aberrant E-cadherin expression. With the antibody that stains the cytoplasmic domain of E-cadherin (clone 36, BD Transduction Laboratories), all 20 cases demonstrated nuclear E-cadherin reactivity, whereas with use of the antibody that recognizes the extracellular domain (clone 36B5, Vector Laboratories), no reactivity was observed in any of the cases. CONCLUSION: This study shows that aberrant beta-catenin and E-cadherin protein expression occurs in 100% of SPT, is probably linked mechanistically to beta-catenin nuclear localization, and two distinct patterns of E-cadherin immunoreactivity are seen in SPT: nuclear (with the antibody against the cytoplasmic domain), or immunonegativity (complete loss) when stained with the antibody for the E-cadherin extracellular fragment.

Squamous cell carcinoma with rhabdoid phenotype and osteoclast-like giant cells in a renal-pancreas transplant recipient.

Squamous cell carcinoma (SCC) is the commonest non-melanotic malignant skin tumour encountered after solid-organ transplantation. In this setting it is associated with a worse prognosis than sun-damage-induced SCC. Rhabdoid cells and osteoclastic giant cells are infrequently seen in SCC. This case highlights the unusual occurrence of rhabdoid cells and osteoclastic giant cells in a post-transplant SCC.

Coeliac disease: an update for pathologists.

Coeliac disease is the manifestation of an immune hypersensitivity reaction towards gluten and related proteins, in genetically predisposed people. Although the precise pathogenesis of this condition remains to be fully elucidated, it is probably multifactorial in origin. The diagnosis of coeliac disease has traditionally depended on intestinal biopsies alone; nowadays, the diagnosis has been expanded to include an array of serological markers. This review is intended to offer pathologists an update of the relevant history and immunopathology pertaining to coeliac disease and also to offer recommendations on the ongoing responsibilities of the pathologist in the diagnosis and reporting of coeliac disease.

Composite adenocarcinoma and large cell neuroendocrine carcinoma of the rectum.

Composite glandular-endocrine tumors of the gastrointestinal tract are rare neoplasms. Even more uncommon are the so-called amphicrine tumors, lesions in which dual epithelial and endocrine differentiation occurs in the same cell. We describe a patient who complained of rectal pain and bleeding with a mixed or composite adenocarcinoma and neuroendocrine carcinoma of the rectum. Histological examination revealed a distinct adenocarcinoma of conventional type with glandular structures admixed intimately with a neuroendocrine carcinoma. The latter component was deeply infiltrative, while the adenocarcinoma occupied the more superficial aspect of the tumor. What was interesting was the immunophenotype of the lesion: cytokeratin (CK) 20 expression was very focal in the adenocarcinoma component and negative in the neuroendocrine carcinoma, while CK 7 was expressed strongly in the adenocarcinoma and only focally in the neuroendocrine component. This cytokeratin profile suggests a possible origin from the anal transitional zone.

Rectal adenocarcinoma with oncocytic features: possible relationship with preoperative chemoradiotherapy.

BACKGROUND: The introduction of preoperative chemoradiation into the treatment protocol of rectal adenocarcinomas has affected the microscopical morphology in subsequent resection specimens. The constellation of histopathological changes is varied and well documented. AIM: To describe oncocytic change in rectal cancers that have been treated with chemoradiation before surgery. METHODS: 7 of 54 patients with rectal cancer were identified with a history of chemoradiation, specifically directed to the rectal tumours in fractions of 4500-5000 cGy of radiation and 5-fluorouracil. The rectal tumours in five of these seven patients were composed of oncocytes that constituted 30-80% of the cancers. The patients were three men and two women aged 65-73 years, all with T3 N0 tumours. The intervals between chemoradiation and resection varied from 3 to 12 weeks. RESULTS: The tumour cells conformed to oncocytes morphologically (large size with abundant, granular eosinophilic cytoplasm, vesicular nuclei and prominent acidophilic nucleoli), immunohistochemically (positive for carcinoembryonic antigen, cytokeratin 20 and caudal type homeo box transcription factor 2, but negative for both chromogranin and synaptophysin) and ultrastructurally (large cells showing tight junctions, cytoplasmic engorgement by mitochondria and absence of neurosecretory granules). CONCLUSIONS: The changes in these cells differ from those described previously in endocrine cells encountered in pretreated rectal cancers. Oncocytic change in this particular clinical context occurs as a reflection of cytotoxic damage or cellular hypoxia induced by chemoradiation resulting in degeneration of the cell and the oncocytic phenotype. Oncocytic change may be an under-recognised histopathological change in rectal cancers receiving preoperative chemoradiation.

Adenosquamous carcinoma of the pancreas with an acantholytic pattern together with osteoclast-like and pleomorphic giant cells.

A 45 year old man presented with abdominal pain, loss of appetite, and significant weight loss over a period of about four weeks. Imaging of the abdomen showed a mass in the region of the head of the pancreas. In view of the size of the mass and the clinical picture, a Whipple's procedure was performed. Histological evaluation of the pancreatic tumour showed an adenosquamous carcinoma (predominantly composed of squamous carcinoma), which was extensively infiltrative with perineural invasion and involvement of peripancreatic lymph nodes. Areas of pancreatic intraepithelial neoplasia grade III and merging of the squamous and adenocarcinoma components were evident. Unusual histological features that characterised this case included a pronounced acantholytic pattern within the squamous carcinoma component, and the presence of both osteoclastic and pleomorphic giant cells. Giant cells have not been documented previously in association with an adenosquamous carcinoma. Although an acantholytic pattern has been noted in squamous carcinomas in other sites, this is the first report of such a pattern in an adenosquamous carcinoma of the pancreas.

Serum resistin is associated with C-reactive protein & LDL cholesterol in type 2 diabetes and coronary artery disease in a Saudi population.

AIMS: Resistin is an adipocyte-derived factor implicated in obesity-associated type 2 diabetes (T2DM). This study examines the association between human serum resistin, T2DM and coronary heart disease. METHODS: One hundred and fourteen Saudi Arabian patients (male: female ratio 46:68; age 51.4 (mean +/- SD)11.7 years; median and range: 45.59 (11.7) years and BMI: 27.1 (mean +/- SD) 8.1 Kgm2 median and range: 30.3 (6.3) were studied. Serum resistin and C-reactive protein (CRP), a marker of inflammation CRP levels, were measured in all subjects. (35 patients had type 2 diabetes mellitus (T2DM); 22 patients had coronary heart disease (CHD). RESULTS: Serum resistin levels were 1.2-fold higher in type 2 diabetes and 1.3-fold higher in CHD than in controls (p = 0.01). In addition, CRP was significantly increased in both T2DM and CHD patients (p = 0.007 and p = 0.002 respectively). The use of regression analysis also determined that serum resistin correlated with CRP levels (p = 0.04, R2 0.045). CONCLUSION: The findings from this study further implicate resistin as a circulating protein associated with T2DM and CHD. In addition this study also demonstrates an association between resistin and CRP, a marker of inflammation in type 2 diabetic patients.

Expression of cell adhesion molecules in oesophageal carcinoma and its prognostic value.

Oesophageal carcinoma remains a disease of poor prognosis. Surgical cure rates are compromised by the fact that most patients are diagnosed at a late stage of disease because of the delayed onset of symptoms, by which time metastases and organ infiltration may have already occurred. Thus, invasion and metastases play a key role in influencing patient survival, and the search for novel treatments may therefore hinge on gaining insight into the mechanisms controlling these processes. It has been established that the initial step in the metastatic cascade is the detachment of tumour cells from the primary tumour via dysregulation of normal cell-cell and cell-matrix interactions. Distinct proteins known as cell adhesion molecules (CAMs) mediate these interactions. In recent years, a plethora of information has contributed to the in depth understanding of these molecules. This review provides a brief description of five families of CAMs (cadherins, integrins, CD44, immunoglobulin superfamily, and selectins) and highlights their altered expression in relation both to prognosis and tumour behaviour in squamous cell carcinoma and adenocarcinoma of the oesophagus.

Aberrations in the mismatch repair genes and the clinical impact on oesophageal squamous carcinomas from a high incidence area in South Africa.

AIMS: To investigate the incidence of genetic aberrations in the DNA repair genes in a cohort of oesophageal cancers. METHODS: One hundred oesophagectomy samples of squamous cell carcinoma were studied. Normal and tumour DNA were isolated using a standard phenol/chloroform extraction procedure. Six recommended microsatellite loci with high informativity were analysed. The following markers were used: D2S123 (2p), D3S659 (3p), D3S1255 (3p), Bat 25 (4q), Bat 26 (2p), and Bat 40 (1p). The results were analysed using software attached to an automated DNA sequencer. The molecular data were then correlated with clinicopathological parameters. RESULTS: The incidence of microsatellite instability and loss of heterozygosity was very low. There was no significant correlation between the clinicopathological and molecular data. However, D2S123 genetic abnormalities were seen more frequently in both moderately and well differentiated tumours than in poorly differentiated tumours (p = 0.033). Follow up data were available for only 67 of the 100 patients. Fifty patients were alive and 17 patients had died. CONCLUSION: Low frequencies of genetic aberrations in these mismatch repair loci are found in squamous carcinomas of the oesophagus from a high incidence area in South Africa.