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A young girl was referred to our Institution for the appearance of a painless soft swelling in the right parietal region of the scalp. In the same site, the patient had a parietal bone fracture 1 year ago. In the suspicion of a growing skull fracture, the patient underwent radiological investigations. Ultrasound showed a soft, poorly vascularised swelling with parenchymatous content. The skull X-ray showed an apparent healing of the previous fracture. CT scan and MRI confirmed the correct healing of the fracture and described the presence of a lipomatous mass. The mass was surgically removed and histology confirmed the diagnosis of encapsulated lipoma. The postoperative period was uneventful, with no evidence of infections or recurrence in the 6-month follow-up.

The identification of mismatch repair deficient (dMMR) and microsatellite unstable (MSI) endometrial cancers (ECs) is important in screening, diagnosis, and therapeutic stratification of patients. We compared the diagnostic performance of 4 MSI molecular tests based on fragment length assay in capillary electrophoresis (OncoMate™ MSI assay, Promega) and in microcapillary electrophoresis (TapeStation 4200, Agilent); with high-resolution melting (HRM) analysis approaches (Idylla™ MSI Test, Biocartis; EasyPGX® ready MSI, Diatech Pharmacogenetics) on a series of 56 ECs, which was well characterized for MMR status with immunohistochemical approach (IHC, nonmolecular reference test). The concordance of fluorescence capillary electrophoresis with IHC (AUC 0.98) was higher respect to the other molecular methodologies. Otherwise, HRM approaches and microcapillary electrophoresis platform failed to detect MSI-ECs showing minimal microsatellite shifts. In conclusion, in colorectal site, several technologies are eligible for MSI test, whereas in ECs, MSI test should be based on fluorescent capillary electrophoresis as it identifies a higher proportion of cases that could be misdiagnosed with other strategies.

Summary Autoimmune cholestatic liver diseases are rare hepato-biliary disorders characterized by a progressive, inflammatory destruction of bile ducts. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. Both may evolve into secondary biliary cirrhosis and its complications. Therapeutic options are limited and liver transplantation remains the only definitive treatment for PBC and PSC. Most PBC and PSC patients have a typical presentation, which does not require liver biopsy. However, in routine clinical practice, important variants or specific subgroups that benefit from liver biopsy for proper management may be observed. Herein, we provide a general overview of clinical and pathological characteristic of PBC and PSC, highlighting the most important features for routine diagnostic practice.

Summary Autoimmune hepatitis (AIH) is a relatively rare non-resolving chronic liver disease, which mainly affects women. It is characterized by hypergammaglobulinemia, circulating autoantibodies, interface hepatitis on liver histology and a favourable response to immunosuppression. The putative mechanism for the development of autoimmune hepatitis is thought to be the interaction between genetic predisposition, environmental triggers and failure of the native immune system. AIH still remains a major diagnostic and therapeutic challenge, mainly because it is a very heterogeneous disease. Prompt and timely diagnosis is crucial since, if left untreated, AIH has a high mortality rate. Histological demonstration of hepatitis is required for the diagnosis of AIH and, therefore, liver biopsy is mandatory in the initial diagnostic work-up, before treatment. In this review, we summarize the histological features of AIH with the main aim of highlighting the most important clinical-pathological hallmarks useful in the routine diagnostic practice.

Background and aims There are several short-term prognostic scores for alcoholic hepatitis (AH) that combine demographical and biochemical parameters. The extent of liver fibrosis may also be relevant to the prognosis of AH with potential added value. We evaluated collagen proportionate area (CPA) as a predictor of short and long-term mortality in AH. Methods We retrospectively included patients with biopsy-verified AH. Clinical, laboratory and outcome data were collected. CPA and five AH scores were calculated: Maddrey's DF, MELD, GAHS, ABIC, and the Lille Model. Predictors of short and long-term all-cause mortality were assessed using Cox regression analysis. Results We included 140 patients with AH. In total, 67 (48%) patients died after a median follow-up of 66 (IQR 102) months, with 17 (12%) dying within the first 90-days. CPA was not a predictor of 90-days mortality and had no additional value to the prognostic AH scores on short-term mortality. However, CPA predicted long-term mortality independently of prognostic AH scores. Importantly, CPA and abstinence from alcohol were independent predictors of long-term mortality in patients alive 90 days after the biopsy. Conclusion CPA predicts long-term mortality in patients with AH independently of abstinence from alcohol but has no prognostic value on short-term mortality.

Background: The histopathologic diagnosis of celiac disease (CD) may be challenging when the duodenal biopsies mucosal injury is limited. Intraepithelial T-lymphocytes (IELs) can be useful to characterize the degree of mucosal inflammation. A small fraction of IELs expresses the γδ T-cell receptor (named γδ-IELs), whose density, determined by flow cytometry or frozen section immunohistochemistry (IHC), is a specific marker for CD. Aim: To establish a new IHC assay for γδ-IELs applicable to formalin-fixed paraffin-embedded (FFPE) duodenal biopsies. Methods: We analyzed γδ-IELs using IHC in 138 duodenal biopsies using a standard IHC staining protocol with a new monoclonal antibody H-41. IELs were quantitated with digital image analysis. Results: Compared to those in non-celiac controls (n = 51), γδ-IEL density was significantly increased in newly diagnosed celiac disease patients (n = 22, p < 0.0001). In ROC-curve analysis, the cutoff of 6.5 γδ-IELs/100 enterocytes distinguished optimally active CD patients from non-celiac controls (sensitivity 96%, specificity 95%). γδ-IEL density in CD patients on a gluten-free diet (n = 53) were also higher than in controls (p < 0.0001), but lower than those in newly diagnosed CD (p < 0.0001). The diagnostic value of γδ-IELs outperformed that of CD3 + IELs in both patient groups. γδ-IELs were better than CD3 + IELs distinguishing between celiac disease and conditions histologically mimicking celiac disease (n = 12). Conclusions: Intraepithelial γδ T-lymphocytes can be stained and quantitated reliably in FFPE duodenal biopsies. The results showed excellent specificity and sensitivity for celiac disease. The new IHC method of detection of γδ-IELs is a promising addition to the routine histopathologic assessment methodology of celiac disease. publishedVersion

Intestinal adenosquamous carcinoma (ASC) is a rare colorectal neoplasm frequently occurring at onset as a locally advanced disease with distant metastases. The liver is the most common site of metastasis, followed by the peritoneum and the lung. Cutaneous metastases from usual colorectal adenocarcinoma occur in about 3% of cases, both at the time of diagnosis in advanced disease and during the follow-up. To the best of our knowledge, skin metastasis from ASC has never been described, and no biological landscape of ASC has ever been investigated. We report a case of synchronous intestinal ASC and cutaneous single facial metastasis in a 70-year-old man with morphological, immunohistochemical, and molecular analysis of primary and metastatic lesions. Primary and metastatic ASC showed the same morphological and immunohistochemical features. Target sequencing analysis revealed, both in primary tumor and metastasis, a pathogenic KRAS gene missense mutation c.38G > A p.(Gly13Asp) and a likely pathogenic CTNNB1 gene missense mutation c.94G > A p.(Asp32Asn). A nuclear localization of β-catenin protein in adenocarcinomatous component of primary and metastatic lesions was observed on immunohistochemistry. We describe a case of single synchronous facial cutaneous metastasis from intestinal ASC showing KRAS and CTNN1B mutations both on primary and metastatic lesions.

Pancreatic ductal adenocarcinoma is a lethal disease for which radical surgery and chemotherapy represent the only curative options for a small proportion of patients. Recently, FOLFIRINOX and nab-paclitaxel plus gemcitabine have improved the survival of metastatic patients but prognosis remains poor. A pancreatic tumor microenvironment is a dynamic milieu of cellular and acellular elements, and it represents one of the major limitations to chemotherapy efficacy. The continued crosstalk between cancer cells and the surrounding microenvironment causes immunosuppression within pancreatic immune infiltrate increasing tumor aggressiveness. Several potential targets have been identified among tumor microenvironment components, and different therapeutic approaches are under investigation. In this article, we provide a qualitative literature review about the crosstalk between the tumor microenvironment components and immune system in pancreatic cancer. Finally, we discuss potential therapeutic strategies targeting the tumor microenvironment and we show the ongoing trials.

Hematopoietic stem cell transplantation (HSCT) recipients have been reported to have an increased risk of chronic graft versus host disease (cGVHD) and hematological and solid cancers. Oral manifestations are the first signs of cGVHD observed in the majority of patients, and oropharyngeal cancer is the most frequent secondary malignancy occurred after HSCT. In this study, we have evaluated the inflammatory infiltrate cell content and correlated with the vascular density in patients affected by primary oral squamous cell carcinoma (OSCC) from previous healthy controls and OSCC after cGVHD. Results have demonstrated that patients with OSCC after GVHD show a more consistent inflammatory infiltrate as compared with the OSCC ones. In detail, the inflammatory background composed of CD3-positive T cells, tryptase-positive mast cells, CD31-positive endothelial cells, and CD68-positive macrophages may be more pronounced in the setting of GVHD + OSCC than in the control group. By contrast, CD20-positive B cells and CD1a-positive dendritic cells were more abundant in the latter population. Finally, a positive correlation was found as between vascular density and inflammatory cell infiltration in both GVHD + OSCC and OSCC groups. Overall, these results confirm the role played by immune cells in enhancing tumor progression and angiogenesis and suggest a potential therapeutic strategy involving inhibition of recruitment of immune cells to the tumor microenvironment and blockade of pro-tumoral effects and pro-angiogenic functions.

Summary Benign biliary tumor are common lesions that are often an incidental finding in subjects who undergo medical imaging tests for other conditions. Most are true neoplasms while few result from reactive or malformative proliferation. Benign tumors have no clinical consequences, although the premalignant nature or potential for malignant transformation is of concern in some cases. The main practical problem for pathologists is the need to differentiate them from malignant biliary tumours, which is not always straightforward. Premalignant lesions of the bile duct have been described, although their incidence has been poorly characterized. These lesions include biliary mucinous cystic neoplasms, intraductal papillary neoplasms of the bile duct, and biliary intraepithelial neoplasia. In this article, histopathology of benign biliary tumors and biliary tumor precursors is discussed, with a focus on the main diagnostic criteria.

Immune-checkpoint inhibitors (ICIs) play a key role in the treatment of advanced stage colorectal cancer (CRC) patients featuring a deficient DNA mismatch repair (dMMR) system or a high microsatellite instability (MSI-H) profile. However, beyond the established role in CRC patients, ICIs have highly proven efficacy in other solid tumors featuring MSI-H/dMMR status represented by endometrial, gastric, ovarian, prostatic, and pancreatic carcinomas (EC, GC, OC, PrC, and PaC). Our aim was to compare the concordance rates among the Idylla™ MSI test, TapeStation 4200, and immunohistochemical (IHC) analysis in assessing MSI-H/dMMR status in EC, GC, OC, PrC, and PaC patients. The Sanger sequencing-based Titano MSI test was used in discordant cases. One hundred and eighty-five cases (n = 40 PrC, n = 39 GC, n = 38 OC, n = 35 PaC, and n = 33 EC) were retrospectively selected. MMR protein expression was evaluated by IHC. After DNA quality and quantity evaluations, the IdyllaTM and TapeStation 4200 platforms were adopted for the evaluation of MSI status. Remarkably, compared to IHC, the Idylla™ platform achieved a global concordance rate of 94.5% (154/163) for the microsatellite stable (MSS)/proficient MMR (pMMR) cases and 77.3% (17/22) for the MSI-H/dMMR cases. Similarly, a global concordance rate of 91.4% (149/163) and 68.2% (15/22) for MSS/pMMR and MSI-H/dMMR cases was also identified between IHC and the TapeStation 4200 microfluidic system. In addition, a global concordance of 93.1% (148/159) and 69.2% (18/26) for MSS/pMMR and MSI-H/dMMR cases was observed between the Idylla™ and TapeStation 4200 platforms. Discordant cases were analyzed using the Titano MSI kit. Overall, our data pinpointed a central role for molecular techniques in the diagnostic evaluation of dMMR/MSI-H status not only in CRC patients but also in other types of solid tumors.

Summary The aim of the study is to evaluate costs of free flap surgery for head and neck (H & N) reconstructions using the time-driven activity-based costing (ABC) method and to compare them with the refund provided by the Italian National Health System (NHS) amounting to 11,891€. We retrospectively selected 29 consecutive patients underwent free flap reconstruction in 2013 at IRCCS Casa Sollievo della Sofferenza. Patients were divided into three groups: Group 1 (n = 10) included patients receiving radial forearm free flap (RFFF), Group 2 (n = 10) receiving anterolateral thigh (ALT) free flap, and Group 3 (n = 9) composed of patients having fibular free flap. For each patient, costs were calculated using the ABC and divided into instay, surgical, and services costs. We observed an overall mean total cost of 27,802.40€. The mean costs related to hospital stay were 9,800.70€. The mean costs for surgery were 13,097.60€ and amounted to 4,904.10€ for services. RFFF appears to be less costing (25,175.40€) compared with ALT (29,191.60€) and fibula free flap (29,040.20€). ABC is an appropriate method to determine actual costs of free flap surgery by correctly allocating the resources used. The Italian NHS tariff seems to be inadequate to cover the real cost of this type of surgery.

Immunohistochemistry (IHC) and polymerase chain reaction (PCR) and fragment separation by capillary electrophoresis represent the current clinical laboratory standard for the evaluation of microsatellite instability (MSI) status. The importance of reporting MSI status in colorectal cancer is based on its potential for guiding treatment and as a prognostic indicator. It is also used to identify patients for Lynch syndrome testing. Our aim was to evaluate pre-analytical factors, such as age of formalin-fixed and paraffin-embedded (FFPE) block, neoplastic cell percentage, mucinous component, and DNA integrity, that may influence the accuracy of MSI testing and assess the concordance between three different MSI evaluation approaches. We selected the mucinous colorectal cancer (CRC) histotype for this study as it may possibly represent an intrinsic diagnostic issue due to its low tumor cellularity. Seventy-five cases of mucinous CRC and corresponding normal colon tissue samples were retrospectively selected. MMR proteins were evaluated by IHC. After DNA quality and quantity evaluation, the Idylla&trade, and TapeStation 4200 platforms were adopted for the evaluation of MSI status. Seventy-three (97.3%) cases were successfully analyzed by the three methodologies. Overall, the Idylla&trade, platform showed a concordance rate with IHC of 98.0% for microsatellite stable (MSS)/proficient MMR (pMMR) cases and 81.8% for MSI/deficient MMR (dMMR) cases. The TapeStation 4200 system showed a concordance rate with IHC of 96.0% for MSS/pMMR cases and 45.4% for MSI/dMMR cases. The concordance rates of the TapeStation 4200 system with respect to the Idylla&trade, platform were 98.1% for MSS profile and 57.8% for MSI profile. Discordant cases were analyzed using the Titano MSI kit. Considering pre-analytical factors, no significant variation in concordance rate among IHC analyses and molecular systems was observed by considering the presence of an acellular mucus cut-off &gt, 50% of the tumor area, FFPE year preparation, and DNA concentration. Conversely, the Idylla&trade, platform showed a significant variation in concordance rate with the IHC approach by considering a neoplastic cell percentage &gt, 50% (p-value = 0.002), and the TapeStation 4200 system showed a significant variation in concordance rate with the IHC approach by considering a DNA integrity number (DIN) &ge, 4 as cut-off (p-value = 0.009). Our data pinpoint a central role of the pre-analytical phase in the diagnostic outcome of MSI testing in CRC.

No prognostic tools are established for alcohol-related liver disease (ALD). Collagen proportionate area (CPA) measurement is a technique that quantifies fibrous tissue in liver biopsies using digital image analysis.To assess the predictive value of CPA on hepatic decompensation and liver-related mortality in ALD METHODS: In a multicentre cohort study, we included 386 patients with biopsy-verified ALD and with long-term follow-up. In the development cohort of 276 patients, we assessed the predictors of hepatic decompensation and liver-related death in standard and competing risk multivariable Cox regression analyses. The results were validated in an independent prospective cohort of 110 patients, where CPA was also correlated with liver stiffness measurement (LSM).In the development cohort, 231 (84%) patients had early/compensated ALD (non-cirrhotic or compensated cirrhosis) and 45 (16%) had decompensated cirrhosis. In the validation cohort, all patients had early/compensated ALD. Independent predictors of liver-related mortality were higher CPA values (HR = 1.04, 95% CI 1.02-1.04) and advanced fibrosis (HR = 2.80, 95% CI 1.29-6.05) with similar results in standard and competing risk multivariable Cox regression analysis. In early/compensated ALD, CPA was the only independent predictor of hepatic decompensation and liver-related death (HR = 1.08, 95% CI 1.06-1.11). In the prospective cohort, we validated that CPA independently predicts hepatic decompensation in early/compensated ALD. The predictive power of CPA and LSM was equally strong.CPA predicts liver-related mortality in ALD and hepatic decompensation and/or liver-related death in early/compensated ALD. Traditional histological assessment may benefit from the addition of CPA to the evaluation of ALD.

Background: The diagnosis of lymphoma requires surgical specimens to perform morphological evaluation, immunohistochemical and molecular analyses. Ultrasound-guided fine needle aspiration may represent an appropriate first approach to obtain cytological samples in impalpable lesions and/or in patients unsuitable for surgical procedures. Although cytology has intrinsic limitations, the cell block method may increase the possibility of achieving an accurate diagnosis. Methods: We retrospectively selected a total of 47 ultrasound-guided fine needle aspiration and drainage samples taken from patients with effusion and deep-seated lesions which are clinically suspicious in terms of malignancy. Results: In 27 cases, both cell block and conventional cytology were performed: 21/27 cell blocks were adequate for the diagnosis of lymphoma and suitable for immunocytochemistry and molecular analyses vs. 12/20 samples to which only conventional cytology was applied. Moreover, in five patients we were able to make a diagnosis of Hodgkin lymphoma with the cell block (CB) technique. Conclusions: Contrary to conventional cytology, the cell block method may allow immunocytochemistry and molecular studies providing useful information for the diagnosis and subtypization of lymphoma in patients unsuitable for surgical procedure or with deep-seated lesions or extra-nodal diseases, additionally, it is a daily, simple and helpful approach. Moreover, we describe the usefulness of cell blocks in the diagnosis of Hodgkin lymphoma.

// Aldo Cavallini 1, * , Maria Teresa Rotelli 2, * , Catia Lippolis 1 , Domenico Piscitelli 3 , Rosa Digennaro 2 , Claudia Covelli 3 , Nicola Carella 1 , Matteo Accetturo 4 and Donato Francesco Altomare 2 1 Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases, IRCCS “Saverio de Bellis”, Castellana Grotte (BA), Italy 2 General Surgery and Liver Transplantation Unit, Department of Emergency and Organ Transplantation (DETO), University of Bari “Aldo Moro”, Bari, Italy 3 Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari “Aldo Moro”, Bari, Italy 4 Nephrology Unit, Department of Emergency and Organ Transplantation (DETO), University of Bari “Aldo Moro”, Bari, Italy * These authors contributed equally to this work Correspondence to: Aldo Cavallini, email: cavaldo@libero.it Keywords: desmoid tumor, microRNA, CTNNB1 mutations, tetraspanin3 (TSPAN3) mRNA, serpin family A member 3 (SERPINA3) mRNA Received: November 16, 2016 Accepted: February 22, 2017 Published: March 19, 2017 ABSTRACT Desmoid tumors (DT) are rare, benign, fibroblastic neoplasm with challenging histological diagnosis. DTs can occur sporadically or associated with the familial adenomatous polyposis coli (FAP). Most sporadic DTs are associated with β-catenin gene ( CTNNB1 ) mutations, while mutated APC gene causes FAP disease. microRNAs (miRNAs) are involved in many human carcinogenesis. The miRNA profile was analyzed by microarray in formalin-fixed, paraffin-embedded (FFPE) specimens of 12 patients (8 sporadic, 4 FAP-associated) and 4 healthy controls. One hundred and one mRNAs resulted dysregulated, of which 98 in sporadic DTs and 8 in FAP-associated DTs, 5 were shared by both tumors. Twenty-six miRNAs were then validated by RT-qPCR in 23 sporadic and 7 FAP-associated DT samples matched with healthy controls. The qPCR method was also used to evaluate the CTNNB1 mutational status in sporadic DTs. The correlation between sporadic DTs and miRNA expression showed that miR-21-3p increased in mutated versus wild-type DTs, while miR-197-3p was decreased. The mRNA expression of Tetraspanin3 and Serpin family A member 3, as miR-21-3p targets, and L1 Cell Adhesion Molecule, as miR-197-3p target, was also evaluate. CTNNB1 mutations associated to miRNA dysregulation could affect the genesis and the progression of this disease and help histological diagnosis of sporadic DTs.

Solid pseudopapillary neoplasms (SPNs) are rare solid pancreatic tumors mainly affecting young women. Despite the high percentage of favorable prognosis, they are considered as low grade malignant neoplasms, and metastases occur in 5%−15% of patients. Almost all SPNs (95%) have somatic activating mutations in the β-catenin gene [1]. β-catenin plays a crucial role in cell proliferation and differentiation via Wnt signaling pathway and interacts with E-cadherin and α-catenin for the regulation of cell adhesion and growth [2]. Another relevant genetic alteration in pancreatic neoplasms is represented by the DNA mismatch repair deficiency (dMMR). dMMR is strongly associated with a microsatellite instability (MSI) status as a result of an alteration in the lengths of microsatellites due to deletion/insertion of repeating units in tumor DNA [3]. dMMR was observed in approximately 1%−2% of patients with pancreatic adenocarcinoma [4]. To date, the “gold standard” for the evaluation of protein integrity of MMR is immunohistochemistry (IHC), showing an analytical sensitivity >90%, specificity of 100% and predictive value of 97% for microsatellite stability (MSS) and 100% for MSI [5]. The study aimed to investigate the expression of MMR proteins and the MSI status in pancreatic SPNs.

The histopathologic diagnosis of celiac disease (CD) may be challenging when the duodenal biopsies mucosal injury is limited. Intraepithelial T-lymphocytes (IELs) can be useful to characterize the degree of mucosal inflammation. A small fraction of IELs expresses the γδ T-cell receptor (named γδ-IELs), whose density, determined by flow cytometry or frozen section immunohistochemistry (IHC), is a specific marker for CD.To establish a new IHC assay for γδ-IELs applicable to formalin-fixed paraffin-embedded (FFPE) duodenal biopsies.We analyzed γδ-IELs using IHC in 138 duodenal biopsies using a standard IHC staining protocol with a new monoclonal antibody H-41. IELs were quantitated with digital image analysis.Compared to those in non-celiac controls (n = 51), γδ-IEL density was significantly increased in newly diagnosed celiac disease patients (n = 22, p 0.0001). In ROC-curve analysis, the cutoff of 6.5 γδ-IELs/100 enterocytes distinguished optimally active CD patients from non-celiac controls (sensitivity 96%, specificity 95%). γδ-IEL density in CD patients on a gluten-free diet (n = 53) were also higher than in controls (p 0.0001), but lower than those in newly diagnosed CD (p 0.0001). The diagnostic value of γδ-IELs outperformed that of CD3 + IELs in both patient groups. γδ-IELs were better than CD3 + IELs distinguishing between celiac disease and conditions histologically mimicking celiac disease (n = 12).Intraepithelial γδ T-lymphocytes can be stained and quantitated reliably in FFPE duodenal biopsies. The results showed excellent specificity and sensitivity for celiac disease. The new IHC method of detection of γδ-IELs is a promising addition to the routine histopathologic assessment methodology of celiac disease.

Human Herpesvirus 8 (HHV8) has been associated with a wide spectrum of B-cell lymphoproliferative disorders, including Primary Effusion Lymphoma, Multicentric Castleman Disease, HHV8-positive Diffuse Large B-cell Lymphoma, not otherwise specified and germinotropic lymphoproliferative disorder. The association of different HHV8-related lymphoproliferative disorders is described in immunodeficient patients. We report a case of Primary Effusion Lymphoma metachronous to Multicentric Castleman Disease in an immunocompetent patient.

Background Collagen proportionate area (CPA) measurement is a technique that quantifies fibrous tissue in liver biopsies by measuring the amount of collagen deposition as a proportion of the total biopsy area. CPA predicts clinical outcomes in patients with HCV and can sub-classify cirrhosis. Aim To test the ability of CPA to quantify fibrosis and predict clinical outcomes in patients with NAFLD. Methods We assessed consecutive patients with biopsy-proven NAFLD from three European centres. Clinical and laboratory data were collected at baseline and at the time of the last clinical follow-up or death. CPA was performed at two different objective magnifications, whole biopsy macro and ×4 objective magnification, named standard (SM) and high (HM) magnification respectively. The correlation between CPA and liver stiffness was assessed in a sub-group of patients. Results Of 437 patients, 32 (7.3%) decompensated and/or died from liver-related causes during a median follow-up of 103 months. CPA correlated with liver stiffness and liver fibrosis stage across the whole spectrum of fibrosis. HM CPA was significantly higher than SM CPA in stages F0-F3 but similar in cirrhosis, reflecting a higher ability to capture pericellular/perisinusoidal fibrosis at early stages. Age at baseline (HR: 1.04, 95% CI: 1.01-1.08), HM CPA (HR: 1.04 per 1% increase, 95% CI: 1.01-1.08) and presence of advanced fibrosis (HR: 15.4, 95% CI: 5.02-47.84) were independent predictors of liver-related clinical outcomes at standard and competing risk multivariate Cox-regression analysis. Conclusions CPA accurately measures fibrosis and is an independent predictor of clinical outcomes in NAFLD; hence it merits further evaluation as a surrogate endpoint in clinical trials.

There is little documented evidence suggesting that liver fat is responsible for liver injury in the absence of other disease processes. We investigated the relationships between liver fat, aminotransferases and hepatic architecture in liver biopsies with simple steatosis. We identified 136 biopsies with simple steatosis from the Royal Free Hospital Archives with both clinical data and sufficient material. Digital image analysis was employed to measure fat proportionate area (mFPA). Hepatocyte area (HA) and lobule radius (LR) were also measured. There were significant increases in ALT (p

Background and Aims. Nonceliac gluten sensitivity (NCGS) is a gluten-related emerging condition. Since few data about NCGS histopathology is available, we assessed the markers of lymphocyte and innate immunity activation. Materials and Methods. We retrieved duodenal biopsy samples of patients with NCGS diagnosis according to the Salerno criteria. We selected specimens of positive (seropositive celiac disease/Marsh 1-2 stage) and negative (normal microscopic picture) controls. Immunohistochemistry for CD3 (intraepithelial lymphocytes-IELs), CD4 (T helper lymphocytes), CD8 (T cytotoxic lymphocytes), and CD1a/CD117 (Langerhans/mast cells) was performed. ANOVA plus Bonferroni’s tests were used for statistical analysis. Results. Twenty NCGS, 16 celiac disease, and 16 negative controls were selected. CD3 in NCGS were higher than negative controls and lower than celiac disease (18.5 ± 6.4, 11.9 ± 2.8, and 40.8 ± 8.1 IELs/100 enterocytes; p<0.001). CD4 were lower in NCGS than controls and celiac disease (31.0 ± 22.1, 72.5 ± 29.5, and 103.7 ± 15.7 cells/mm2; p<0.001). CD8 in NCGS were similar to negative controls, but lower than celiac disease (14.0 ± 7.4 and 34.0 ± 7.1 IELs/100 enterocytes, p<0.001). CD117 were higher in NCGS than celiac disease and negative controls (145.8 ± 49.9, 121.3 ± 13.1, and 113.5 ± 23.4 cells/mm2; p=0.009). Conclusions. The combination of CD4 and CD117, as well as IEL characterization, may be useful to support a clinical diagnosis of NCGS.

Aim of this chapter is to investigate the phenomenon of the social construction of the "bad woman". During the twentieth century the Italian crime news is populated by dark ladies: infanticides, murderous lovers, witches and wives with a disquieting double life. From these criminal court cases emerged the image of an Italy in transformation, and they became an interesting historical source to investigate the progressive rise on the public scene of an unprecedented visibility of the female body, icon and allegory of the Nation. The essay highlights the continuity and discontinuity between these portraits of unknown women entered in the public arena through the particular channel of the crime news, pointing out the archetypes and the elements of currents that emerge from the narration of the tragic events in which they are the absolute protagonists.

Mucormycosis are an emerging group of life-threatening fungal infections caused by filamentous fungi of the Mucorales family. Mucormycosis are most common in stem-cell transplant recipients and patients with underlying hematologic malignancies, poorly controlled diabetes mellitus, trauma, neutropenia, corticosteroid and deferoxamine therapy due to deficiency of phagocytic function, elevated serum levels of available iron and host-pathogen interaction. The fungi penetrate blood vessels causing endothelial damage and extensive angioinvasion with infarction, necrosis, and thrombosis of different tissues. Mucormycosis carries a very high mortality in cases of pulmonary disease, with even higher rates when there is difficulty establishing the diagnosis. We present a case of 67-year-old man with pulmonary form of mucormycosis presenting as opportunistic infection post induction chemotherapy for acute myeloid leukemia FAB M2. We treated the patient with intravenous amphotericin B for 4 weeks and endobronchial resection, after which he clinically and radiographically improved. Overall, early consideration of mucormycosis can lead to an earlier diagnosis, medical and surgical therapy, and an increased survival rate. Furthermore, we provide a real example of multiple thinking strategies, needed for a patient oriented clinical practice. Overall, this case is a challenging example between clinical judgment and available validated guidelines.

Goblet cell carcinoid of the ovary is a very rare histological cell type with uncertain biological behaviour. It is usually a metastatic tumour from the gastrointestinal tract, especially from the ...

AIM To evaluate mucosal baseline mRNA expression of tissue transglutaminase 2 (tTG2), interferon gamma (IFNγ), toll-like receptor 2 (TLR2) and Myeloid Differentiation factor 88 (MyD88) in patients with microscopic enteritis (ME). METHODS We retrospectively enrolled 89 patients with ME of different etiology, which was defined within a 2-year mean period of follow-up. Baseline histological examination was performed on Hematoxylin-Eosin stained sections and CD3 lymphocyte immunohistochemistry was used for intraepithelial lymphocyte count (IELs). ME was defined according to the criteria of Bucharest Consensus Conference. For each patient, formalin embedded biopsy samples of the duodenum referred to the period of ME diagnosis were retrieved. Real-time polymerase chain reaction (RT-PCR) was used to detect the amount of mRNA coding for tTG2, IFNγ, TLR2 and MyD88, and the quantity was expressed as fold change compared to controls. Control group was represented by duodenal normal specimens from 15 healthy subjects undergoing endoscopy for functional symptoms. Comparisons among continuous variables were performed by One way analysis of variance (ANOVA) and Bonferroni’s test. The χ2 test was used for categorical variables. Pearson’s test was used to evaluate correlations. Receiver operating curves were drawn for all four markers to estimate sensitivity and specificity in discriminating the development of CD and GS. RESULTS After a period of follow up of 21.7 ± 11.7 mo, the following diagnoses were achieved: gluten related disorders in 48 subjects (31 CD; 17 GS) and non-gluten related ones in 41 (29 Irritable Bowel Syndrome - IBS; 12 Others). CD patients had the highest tTG2 levels (8.3 ± 4.5). The ANOVA plus Bonferroni analysis showed that CD > Other ME > GS = IBS > negative controls. A cut off value of 2.258 was able to discriminate between CD and GS with a sensitivity of 52.94% and a specificity of 87.1%. Additionally, CD patients had the highest IFNγ levels (8.5 ± 4.1). ANOVA plus Bonferroni demonstrated CD > Other ME > GS = IBS > negative controls. A cut off of 1.853 was able to differentiate CD and GS with a sensitivity of 47.06% and a specificity of 96.77%. Patients with non gluten-related causes of ME exhibited the highest TLR2 levels (6.1 ± 1.9) as follows: Other ME > CD = GS = IBS > negative controls. TLR2 was unable to discriminate CD from GS. Patients with CD overexpressed MyD88 levels similarly to non gluten-related causes of DL (7.8 ± 4.9 and 6.7 ± 2.9), thus CD = Other ME > GS = IBS > negative controls. A cut off of 3.722 was able to differentiate CD from GS with a sensitivity of 52.94% and a specificity of 74.19%. IELs count (15-25 and more than 25/100 enterocytes) strongly correlated with mRNA levels of all tested molecules (P < 0.0001). CONCLUSION Our results confirm that a single marker is unable to predict a discrimination among ME underlying conditions as well as between CD and GS. Mucosal high levels of tTG and IFNγ mRNA may predict the development of CD more than GS with high specificity, despite an expected low sensitivity. TLR2 does not discriminate the development of CD from GS. MyD88 levels indicate that intestinal permeability is more increased when a severe intestinal damage underlies ME in both gluten related and unrelated conditions. Therefore, the results of the present paper do not seem to show a clear translational value.

Background. Dopa-negative, inactive melanocytes, present in the middle portion of the hair follicle, but also in hair bulbs, have been reported as a source of pigment cells, when repopulation of epidermal melanocytes occurs. A melanocyte reservoir in these anatomical sites has been suggested. Our objective was to investigate the ability of the lower third of the hair follicle (hair bulb) to repigment achromic skin in vitiligo. Methods. Scalp hair bulbs were transplanted within leukodermic areas in 10 patients with vitiligo. Results. Repigmentation around the grafts was suitable for evaluation in four cases. Dopa-positive (+) cells were seen in the epidermal basal cell layer of the repigmented areas. Conclusions. Although these findings were observed only in a few patients, they suggest that melanocytes from the implanted lower third portion of the hair follicle (hair bulb) act as a reservoir in this anatomic location and are able to migrate and repigment achromic areas in vitiligo.

Selective IgM deficiency (sIGMD) is very rare; it may be associated with celiac disease (CD). We present the case of an 18-year-old man with sIGMD masking seronegative CD. Symptoms included abdominal pain, diarrhea and weight loss. Laboratory tests showed reduced IgM, DQ2-HLA and negative anti-transglutaminase. Villous atrophy and diffuse immature lymphocytes were observed at histology. Tissue transglutaminase mRNA mucosal levels showed a 6-fold increase. The patient was treated with a gluten-free diet (GFD) and six months later the symptoms had disappeared, the villous architecture was restored and mucosal tissue transglutaminase mRNA was comparable to that of healthy subjects. After 1 year of GFD, a complete restoration of normal IgM values was observed and duodenal biopsy showed a reduction of immature lymphocytes and normal appearance of mature immune cells.

Objective To characterize the epidemiological, clinical, and histopathological features of patients with cancer who develop widespread polymorphic and pruritic skin lesions following radiotherapy. Patients, Design, and Interventions During phase 1, epidemiological and clinical features of 103 patients with cancer, 83 treated with radiotherapy (71 women and 12 men) and 20 controls who did not undergo radiotherapy (16 women and 4 men), were explored during 3 months (October 1995 to January 1996). During phase 2, in 30 additional patients with cancer who were treated with telecobalt or linear accelerator, 18 with skin lesions (15 women and 3 men) and 12 without lesions (10 women and 2 men), the following were investigated: (1) hematoxylin-eosin–stained sections for routine histopathological examination and direct immunofluorescence, and lymphocytic markers; (2) blood, skin, and primary tumor eosinophilia; and (3) the presence of antiepidermal autoantibodies. Patients were examined during 5 months (February 1996 to June 1996). Setting A dermatology department at a university hospital. Results During phase 1, 14 (17%) of the 83 patients undergoing radiotherapy developed an eruption. Acral excoriations, erythematous papules, vesicles, and bullae were the most frequent lesions. During phase 2, in 18 patients, a superficial and deep lymphocytic perivascular infiltrate with numerous eosinophils, intraepidermal and interstitial eosinophilic infiltrates, eosinophilic panniculitis, IgM and C3 perivascular deposits, and slightly predominant CD4 + cells were observed. No antiepidermal autoantibodies were found. Conclusions The clinical, histopathological, and immunopathologic features in patients with cancer undergoing radiotherapy are described. To our knowledge, this condition has not been well characterized. Because of its unique presentation, the denomination "eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy" is suggested.