Publications by authors named "Alessandro Vanoli"

109 Publications

Diagnostic delay and misdiagnosis in eosinophilic oesophagitis.

Dig Liver Dis 2021 Jun 8. Epub 2021 Jun 8.

Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy. Electronic address:

Background: Eosinophilic oesophagitis (EoE) may lead to severe complications if not promptly recognised.

Aims: To assess the diagnostic delay in patients with EoE and to explore its risk factors.

Methods: EoE patients followed-up at eight clinics were included via retrospective chart review. Diagnostic delay was estimated as the time lapse occurring between the appearance of the first likely symptoms indicative of EoE and the final diagnosis. Patient-dependent and physician-dependent diagnostic delays were assessed. Multivariable regression models were computed.

Results: 261 patients with EoE (mean age 34±14 years; M:F ratio=3:1) were included. The median overall diagnostic delay was 36 months (IQR 12-88), while patient- and physician-dependent diagnostic delays were 18 months (IQR 5-49) and 6 months (IQR 1-24). Patient-dependent delay was greater compared to physician-dependent delay (95% CI 5.1-19.3, p<0.001). A previous misdiagnosis was formulated in 109 cases (41.8%; gastro-oesophageal reflux disease in 67 patients, 25.7%). The variables significantly associated with greater overall diagnostic delay were being a non-smoker, >1 episode of food impaction, previous endoscopy with no biopsies, regurgitation, and ≥2 assessing physicians. Being single was significantly associated with lower overall and patient-dependent diagnostic delay.

Conclusion: EoE is burdened by substantial diagnostic delay, depending on both patient-related and physician-related factors.
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http://dx.doi.org/10.1016/j.dld.2021.05.017DOI Listing
June 2021

Serum Markers of Refractoriness and Enteropathy-Associated T-Cell Lymphoma in Coeliac Disease.

Cancers (Basel) 2021 May 11;13(10). Epub 2021 May 11.

Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, 27100 Pavia, Italy.

The persistence or recurrence of symptoms in patients with coeliac disease (CD), despite a gluten-free diet (GFD), must prompt further work-up for excluding refractory CD (RCD). The aim of this study was to assess the accuracy of serum markers in predicting refractoriness in CD patients. This study included 72 patients affected by CD followed-up at our center, namely 49 uncomplicated CD before and after GFD and 23 RCD. Serum levels of chromogranin A (CgA) and β2-microglobuline were measured at baseline and at follow-up (median time of 13 months) in each group of patients. Cut-off points for each marker were estimated to differentiate RCD from uncomplicated CD patients. Serum levels of CgA and β2-microglobuline were significantly higher in patients with RCD compared to uncomplicated CD ( < 0.001), both at baseline and at follow-up, with no significant difference between RCD type 1 and type 2. The estimated cut-off point for CgA was 90.2 ng/mL (sensitivity 83%, specificity 100%), while for β2-microglobuline it was 696 mcg/L (sensitivity 100%, specificity of 100%). To conclude, CgA and β2-microglobuline could be useful serological markers of refractoriness in CD, with the ability to discriminate those patients who should undergo upper gastrointestinal endoscopy for making a definite diagnosis.
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http://dx.doi.org/10.3390/cancers13102289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151476PMC
May 2021

Prognostic relevance and putative histogenetic role of cytokeratin 7 and MUC5AC expression in Crohn's disease-associated small bowel carcinoma.

Virchows Arch 2021 May 8. Epub 2021 May 8.

Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Via Carlo Forlanini 16 -, 27100, Pavia, Italy.

Most Crohn's disease-associated small bowel carcinomas (CrD-SBCs) are diagnosed in advanced stage and have poor prognosis. To improve diagnosis and therapy, a better knowledge of tumour precancerous lesions, histotypes and prognostic factors is needed. We investigated histologically and immunohistochemically 52 CrD-SBCs and 51 small bowel carcinomas unrelated to inflammatory disease, together with their tumour-associated mucosa, looking for Crohn-selective changes. Histologic patterns and phenotypic markers potentially predictive of CrD-SBC histogenesis and prognosis were analysed. Cytokeratin 7 or MUC5AC-positive metaplastic changes were found in about half of investigated CrD-SBCs, significantly more frequently than in CrD-unrelated SBCs. They correlated with metaplastic changes of their associated mucosa, while being absent in normal ileal mucosa. Histologic patterns suggestive for progression of some cytokeratin 7 and/or MUC5AC-positive metaplastic lesions into cancer of the same phenotype were also observed. Patient survival analyses showed that tumour cytokeratin 7 or MUC5AC expression and non-cohesive histotype were adverse prognostic factors at univariable analysis, while cytokeratin 7 and non-cohesive histotype were also found to predict worse survival in stage- and age-inclusive multivariable analyses. Besides conventional dysplasia, hyperplasia-like non-conventional lesions were observed in CrD-SBC-associated mucosa, with patterns suggestive for a histogenetic link with adjacent cancer. In conclusion the cytokeratin 7 and/or MUC5AC-positive metaplastic foci and the non-conventional growths may have a role in cancer histogenesis, while tumour cytokeratin 7 and non-cohesive histotype may also predict poor patient survival. Present findings are worth being considered in future prospective histogenetic and clinical studies.
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http://dx.doi.org/10.1007/s00428-021-03109-2DOI Listing
May 2021

Small Bowel Epithelial Precursor Lesions: A Focus on Molecular Alterations.

Int J Mol Sci 2021 Apr 22;22(9). Epub 2021 Apr 22.

Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, 27100 Pavia, Lombardy, Italy.

The wider use of gastrointestinal endoscopic procedures has led to an increased detection of small intestinal preneoplastic and neoplastic epithelial lesions, most of which are identified in the duodenum and ampullary region. Like their malignant counterparts, small intestinal glandular precursor lesions, which include adenomas and hamartomas, may arise sporadically or be associated with hereditary tumor syndromes, such as familial adenomatous polyposis, -associated polyposis, Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and Cowden syndrome. In addition, dysplastic, preinvasive lesions have been observed adjacent to small bowel adenocarcinomas complicating immune-related disorders, such as celiac or Crohn's disease. Adenomatous lesions may exhibit an intestinal-type, gastric-type, or, very rarely, serrated differentiation, related to different molecular pathogenetic mechanisms. Finally, in the background of multiple endocrine neoplasia 1 syndrome, precursor neuroendocrine growths have been described. In this review we offer a comprehensive description on the histo-molecular features of the main histotypes of small bowel epithelial precursors lesions, including: (i) sporadic adenomas (intestinal-type and gastric-type; non-ampullary and ampullary); (ii) syndromic adenomas; (iii) small bowel dysplasia in celiac and Crohn's disease; (iv) serrated lesions; (v) hamartomatous lesions; and (vi) neuroendocrine precursor lesions.
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http://dx.doi.org/10.3390/ijms22094388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122855PMC
April 2021

Histologic heterogeneity and syndromic associations of non-ampullary duodenal polyps and superficial mucosal lesions.

Dig Liver Dis 2021 Apr 1. Epub 2021 Apr 1.

First Department of Internal Medicine, University of Pavia, IRCCS San Matteo Hospital Foundation, Viale Golgi 19, 27100, Italy.

Background: Duodenal polyps and superficial mucosal lesions (DP/SMLs) are poorly characterised.

Aims: To describe a series of endoscopically-diagnosed extra-ampullary DPs/SMLs.

Methods: This is a retrospective study conducted in a tertiary referral Endoscopy Unit, including patients who had DPs or SMLs that were biopsied or removed in 2010-2019. Age, gender, history of familial polyposis syndromes, DP/SML characteristics were recorded. Histopathological, immunohistochemical and molecular analyses were performed.

Results: 399 non-ampullary DP/SMLs from 345 patients (60.6% males; median age 67 years) were identified. Gastric foveolar metaplasia represented the most frequent histotype (193 cases, 48.4%), followed by duodenal adenomas (DAs; 77 cases, 19.3%). Most DAs (median size 6 mm) were sessile (Paris Is; 48%), intestinal-type (96.1%) with low-grade dysplasia (93.5%). Among syndromic DAs (23%), 15 lesions occurred in familial adenomatous polyposis 1, two were in MUTYH-associated polyposis and one was in Peutz-Jeghers syndrome (foveolar-type, p53-positive, low-grade dysplasia). Only one (3.3%) tubular, low-grade DA showed mismatch repair deficiency (combined loss of MLH1 and PMS2, heterogeneous MSH6 expression), and it was associated with a MLH1 gene germline mutation (Lynch syndrome).

Conclusion: DPs/SMLs are heterogeneous lesions, most of which showing foveolar metaplasia, followed by low-grade, intestinal-type, non-syndromic DAs. MMR-d testing may identify cases associated with Lynch syndrome.
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http://dx.doi.org/10.1016/j.dld.2021.03.011DOI Listing
April 2021

Rectal neuroendocrine cell proliferation in a patient with ulcerative colitis treated with adalimumab.

Eur J Gastroenterol Hepatol 2021 May;33(5):766-768

Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1097/MEG.0000000000002089DOI Listing
May 2021

Neuroendocrine neoplasms of the appendix, colon and rectum.

Pathologica 2021 Feb;113(1):19-27

Department of Oncology, University of Turin, Orbassano, Turin, Italy.

Neuroendocrine neoplasms of the appendix, colon and rectum are classified according to the most recent WHO classification as neuroendocrine tumors (NET), neuroendocrine carcinomas (NEC) and mixed neuroendocrine-non neuroendocrine neoplasms (MiNENs). NECs and MiNENs are aggressive neoplasms requiring multimodal treatment strategies. By contrast, NETs are, in most cases, indolent lesions occurring as incidental findings in the appendix or as polyps in the rectum. While most appendiceal and rectal NETs are considered relatively non-aggressive neoplasms, a few cases, may show a more aggressive clinical course. Unfortunately, clinical/pathological characteristics to select patients at high risk of recurrence/metastases are poorly consolidated. Diagnosis is generally easy and supported by the combination of morphology and immunohistochemistry. Differential diagnostic problems are for NECs/MiNENs with poorly differentiated adenocarcinomas, when immunohistochemical neuroendocrine markers are not obviously positive, whereas for NETs they are represented by the rare appendiceal tubular and clear cell variants (which may be confused with non-neuroendocrine cancers) and rectal L-cell tumors which may be chromogranin negative and prostatic marker positive.
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http://dx.doi.org/10.32074/1591-951X-230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138694PMC
February 2021

Neuroendocrine neoplasms of the duodenum, ampullary region, jejunum and ileum.

Pathologica 2021 Feb;113(1):12-18

Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy.

Neuroendocrine neoplasms of the small intestine are some of the most frequently occurring along the gastrointestinal tract, even though their incidence is extremely variable according to specific sites. Jejunal-ileal neuroendocrine neoplasms account for about 27% of gastrointestinal NETs making them the second most frequent NET type. The aim of this review is to classify all tumors following the WHO 2019 classification and to describe their pathologic differences and peculiarities.
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http://dx.doi.org/10.32074/1591-951X-228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138699PMC
February 2021

Neuroendocrine neoplasms of the esophagus and stomach.

Pathologica 2021 Feb;113(1):5-11

Institute of Pathology, University Hospital and University of Lausanne, Switzerland.

Esophageal neuroendocrine neoplasms (E-NENs) are much rarer than other gastro-entero-pancreatic neuroendocrine neoplasms, the majority showing aggressive behavior with early dissemination and poor prognosis. Among E-NENs, exceptionally rare well differentiated neuroendocrine tumors (E-NET) and more frequent esophageal poorly differentiated neuroendocrine carcinomas (E-NEC) and mixed neuroendocrine-non neuroendocrine neoplasms (MiNEN) can be recognized. E-NECs usually exhibit a small cell morphology or mixed small and large cells. Esophageal MiNEN are composed of NEC component admixed with adenocarcinoma or squamous cell carcinoma. Gastric (G) NENs encompass a wide spectrum of entities ranging from indolent G-NETs to highly aggressive G-NECs and MiNENs. Among G-NETs, ECL-cell NETs are the most common and, although composed of histamine-producing cells, are a heterogeneous group of neoplastic proliferations showing different clinical and prognostic features depending on the patient's clinico-pathological background including the morphology of the peri-tumoral mucosa, gastrin serum levels, presence or absence of antral G-cell hyperplasia, and presence or absence of MEN1 syndrome. In general, NET associated with hypergastrinemia show a better outcome than NET not associated with hypergastrinemia. G-NECs and MiNENs are aggressive neoplasms more frequently observed in males and associated with a dismal prognosis.
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http://dx.doi.org/10.32074/1591-951X-229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138695PMC
February 2021

Primary appendiceal-type goblet cell adenocarcinoma of the ileum mimicking an inflammatory stricture in a woman with Crohn's disease.

Dig Liver Dis 2021 Apr 23;53(4):506-508. Epub 2021 Jan 23.

Anatomic Pathology Unit, IRCCS San Matteo Hospital Foundation, Pavia, Italy; Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1016/j.dld.2021.01.005DOI Listing
April 2021

Depletion of circulating IgM memory B cells predicts unfavourable outcome in COVID-19.

Sci Rep 2020 11 30;10(1):20836. Epub 2020 Nov 30.

Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.

Impaired immune responses have been hypothesised to be a possible trigger of unfavourable outcomes in coronavirus disease 2019 (COVID-19). We aimed to characterise IgM memory B cells in patients with COVID-19 admitted to an internal medicine ward in Northern Italy. Overall, 66 COVID-19 patients (mean age 74 ± 16.6 years; 29 females) were enrolled. Three patients (4.5%; 1 female) had been splenectomised and were excluded from further analyses. Fifty-five patients (87.3%) had IgM memory B cell depletion, and 18 (28.6%) died during hospitalisation (cumulative incidence rate 9.26/100 person-week; 5.8-14.7 95% CI). All patients who died had IgM memory B cell depletion. A superimposed infection was found in 6 patients (9.5%), all of them having IgM memory B cell depletion (cumulative incidence rate 3.08/100 person-week; 1.3-6.8 95% CI). At bivariable analyses, older age, sex, number of comorbidities, and peripheral blood lymphocyte count < 1500/µl were not correlated with IgM memory B cell depletion. A discrete-to-marked reduction of the B-cell compartment was also noticed in autoptic spleen specimens of two COVID-19 patients. We conclude that IgM memory B cells are commonly depleted in COVID-19 patients and this correlates with increased mortality and superimposed infections.
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http://dx.doi.org/10.1038/s41598-020-77945-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705651PMC
November 2020

Small Bowel Adenocarcinomas Featuring Special AT-Rich Sequence-Binding Protein 2 (SATB2) Expression and a Colorectal Cancer-Like Immunophenotype: A Potential Diagnostic Pitfall.

Cancers (Basel) 2020 Nov 19;12(11). Epub 2020 Nov 19.

Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Lombardy, Italy.

Special AT-rich sequence-binding protein 2 (SATB2) is a transcription factor expressed by colonic cryptic epithelium and epithelial neoplasms of the lower gastrointestinal (GI) tract, as well as by small bowel adenocarcinomas (SBAs), though at a lower rate. Nevertheless, up to now, only small SBA series, often including a very limited number of Crohn's disease-associated SBAs (CrD-SBAs) and celiac disease-associated SBAs (CD-SBA), have been investigated for SATB2 expression. We evaluated the expression of SATB2 and other GI phenotypic markers (cytokeratin (CK) 7 and CK20, caudal type homeobox 2 (CDX2) and alpha-methylacyl-CoA racemase (AMACR)), as well as mismatch repair (MMR) proteins, in 100 SBAs, encompassing 34 CrD-SBAs, 28 CD-SBAs and 38 sporadic cases (Spo-SBAs). Any mutual association and correlation with other clinico-pathologic features, including patient prognosis, were searched. Twenty (20%) SATB2-positive SBAs (4 CrD-SBAs, 7 CD-SBAs and 9 Spo-SBAs) were identified. The prevalence of SATB2 positivity was lower in CrD-SBA (12%) in comparison with both CD-SBAs (25%) and Spo-SBAs (24%). Interestingly, six SBAs (two CD-SBAs and four Spo-SBAs) displayed a full colorectal carcinoma (CRC)-like immunoprofile (CK7-/CK20+/CDX2+/AMACR+/SATB2+); none of them was a CrD-SBA. No association between SATB2 expression and MMR status was observed. Although SATB2-positive SBA patients showed a more favorable outcome in comparison with SATB2-negative ones, the difference did not reach statistical significance. When cancers were stratified according to CK7/CK20 expression patterns, we found that CK7-/CK20- SBAs were enriched with MMR-deficient cases (71%) and patients with CK7-/CK20- or CK7-/CK20+ SBAs had a significantly better survival rate compared to those with CK7+/CK20- or CK7+/CK20+ cancers ( = 0.002). To conclude, we identified a small (6%) subset of SBAs featuring a full CRC-like immunoprofile, representing a potential diagnostic pitfall in attempts to identify the site of origin of neoplasms of unknown primary site. In contrast with data on colorectal carcinoma, SATB2 expression is not associated with MMR status in SBAs. CK patterns influence patient survival, as CK7-/CK20- cancers show better prognosis, a behavior possibly due to the high rate of MMR-deficient SBAs within this subgroup.
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http://dx.doi.org/10.3390/cancers12113441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699330PMC
November 2020

Malignant epithelial/exocrine tumors of the pancreas.

Pathologica 2020 Sep;112(3):210-226

Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.

Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided.
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http://dx.doi.org/10.32074/1591-951X-167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931574PMC
September 2020

Celiac disease: histology-differential diagnosis-complications. A practical approach.

Pathologica 2020 Sep;112(3):186-196

Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.

Celiac disease is a multi-factorial chronic inflammatory intestinal disease, characterized by malabsorption resulting from mucosal injury after ingestion of wheat gluten or related rye and barley proteins. Inappropriate T-cell-mediated immune response against ingested gluten in genetically predisposed people, leads to characteristic histological lesions, as villous atrophy and intraepithelial lymphocytosis. Nevertheless, celiac disease is a comprehensive diagnosis with clinical, serological and genetic characteristics integrated with histological features. Biopsy of duodenal mucosa remains the gold standard in the diagnosis of celiac disease with the recognition of the spectrum of histological changes and classification of mucosa damage based on updated Corazza-Villanacci system. Appropriate differential diagnosis evaluation and clinical context also for the diagnosis of complications is, moreover, needed for correct histological features interpretation and clinical management.
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http://dx.doi.org/10.32074/1591-951X-157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931573PMC
September 2020

Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes.

Pathologica 2020 Sep;112(3):166-185

Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy.

Gastric cancer accounts for about 6% of cancers worldwide, being the fifth most frequently diagnosed malignancy and the third leading cause of cancer related death. Gastric carcinogenesis is a multistep and multifactorial process and is the result of the complex interplay between genetic susceptibility and environmental factors. The identification of predisposing conditions and of precancerous lesions is the basis for screening programs and early stage treatment. Furthermore, although most gastric cancers are sporadic, familial clustering is observed in up to 10% of patients. Among them, hereditary cases, related to known cancer susceptibility syndromes and/or genetic causes are thought to account for 1-3% of all gastric cancers. The pathology report of gastric resections specimens therefore requires a standardized approach as well as in depth knowledge of prognostic and treatment associated factors.
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http://dx.doi.org/10.32074/1591-951X-166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931572PMC
September 2020

Neoplastic and pre-neoplastic lesions of the oesophagus and gastro-oesophageal junction.

Pathologica 2020 Sep;112(3):138-152

Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy.

Oesophageal and gastro-oesophageal junction (GOJ) neoplasms, and their predisposing conditions, may be encountered by the practicing pathologist both as biopsy samples and as surgical specimens in daily practice. Changes in incidence of oesophageal squamous cell carcinomas (such as a decrease in western countries) and in oesophageal and GOJ adenocarcinomas (such as a sharp increase in western countries) are being reported globally. New modes of treatment have changed our histologic reports as specific aspects must be detailed such as in post endoscopic resections or with regards to post neo-adjuvant therapy tumour regression grades. The main aim of this overview is therefore to provide an up-to-date, easily available and clear diagnostic approach to neoplastic and pre-neoplastic conditions of the oesophagus and GOJ, based on the most recent available guidelines and literature.
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http://dx.doi.org/10.32074/1591-951X-164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931575PMC
September 2020

Comment on Jun, S.Y.; et al. "Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma" 2020, , 2199.

Cancers (Basel) 2020 Oct 15;12(10). Epub 2020 Oct 15.

First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.

We read with interest the paper by Jun S [...].
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http://dx.doi.org/10.3390/cancers12102982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602438PMC
October 2020

Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas.

Ann Surg Oncol 2021 Feb 5;28(2):1167-1177. Epub 2020 Aug 5.

Unit of Pathology, Cervello Hospital, Palermo, Italy.

Background: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer.

Patients And Methods: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability.

Results: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status.

Conclusions: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.
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http://dx.doi.org/10.1245/s10434-020-08926-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801310PMC
February 2021

ASO Author Reflections: Prognostication in Early- and Advanced-Stage Small Bowel Adenocarcinomas.

Ann Surg Oncol 2020 Dec 28;27(Suppl 3):857-858. Epub 2020 Jul 28.

Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy.

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http://dx.doi.org/10.1245/s10434-020-08936-2DOI Listing
December 2020

Survival in Crohn's disease-associated small bowel adenocarcinoma.

Gut 2021 May 24;70(5):997-998. Epub 2020 Jul 24.

First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

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http://dx.doi.org/10.1136/gutjnl-2020-322364DOI Listing
May 2021

Epstein-Barr virus negative smooth muscle neoplasm of the stomach in a young woman.

Clin Res Hepatol Gastroenterol 2021 Jan 18;45(1):101471. Epub 2020 Jun 18.

Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San-Matteo Hospital, Via Carlo-Forlanini 16, 27100 Pavia, Italy.

Gastric smooth muscle neoplasms are rare and poorly investigated malignancies. Their importance relies on differential diagnosis with more frequent neoplasms(e.g. GIST), on their often mild and deceitful clinical presentation and on their heterogeneous outcome. Moreover, the pathogenesis of gastric leiomyosarcoma seems to point to some acknowledged oncogenic factors such as radiations or oncogenic viral infections. Herein, we describe a case of metastatic gastric leiomyosarcoma in a young woman, previously diagnosed with acute lymphoblastic leukemia treated with chemoradiotherapy.
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http://dx.doi.org/10.1016/j.clinre.2020.05.019DOI Listing
January 2021

Deregulation of miRNAs-cMYC circuits is a key event in refractory celiac disease type-2 lymphomagenesis.

Clin Sci (Lond) 2020 05;134(10):1151-1166

Center for the Prevention and Diagnosis of Celiac Disease, Division of Gastroenterology and Endoscopy, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

A percentage of celiac disease (CD) patients develop refractory type-2 disease (RCD2), a condition associated with increased risk of enteropathy-associated T-cell-lymphoma (EATL) and without therapeutic option. Therefore, we profiled the miRNome in series of peripheral T-cell lymphomas (PTCLs), CD, RCD1 or 2 and in the murine interleukin-15 (IL15)-transgenic (TG) model of RCD. The transcriptome was analyzed in 18 intestinal T-cell lymphomas (ITLs). Bioinformatics pipelines provided significant microRNA (miRNA) lists and predicted targets that were confirmed in a second set of patients. Our data show that ITLs have a unique miRNA profile with respect to other PTCLs. The c-MYC regulated miR-17/92 cluster distinguishes monomorphic epitheliotropic ITL (MEITL) from EATL and prognosticates EATL outcome. These miRNAs are decreased in IL15-TG mice upon Janus kinase (JAK) inhibition. The random forest algorithm identified a signature of 38 classifier miRNAs, among which, the miR-200 and miR-192/215 families were progressively lost in RCD2 and ITL-CD, whereas miR-17/92 and C19MC miRNAs were up-regulated. Accordingly, SMAD3, MDM2, c-Myc and activated-STAT3 were increased in RCD2 and EATL tissues while JAK inhibition in IL15-TG mice restored their levels to baseline. Our data suggest that miRNAs circuit supports activation of STAT3 and c-Myc oncogenic signaling in RCD2, thus contributing to lymphomagenesis. This novel understanding might pave the way to personalized medicine approaches for RCD and EATL.
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http://dx.doi.org/10.1042/CS20200032DOI Listing
May 2020

Long Survival and Prolonged Remission after Surgery and Chemotherapy in a Metastatic Mismatch Repair Deficient Pancreatic Neuroendocrine Carcinoma with MLH1/PMS2 Immunodeficiency and Minimal Microsatellite Shift.

Endocr Pathol 2020 Dec;31(4):411-417

Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Pancreatic neuroendocrine carcinomas (NECs) are rare and very aggressive neoplasms with dismal prognosis, especially when metastatic or with negative prognostic factors, such as vascular invasion. To the best of our knowledge, no case of pancreatic NEC with mismatch repair deficiency has been reported to date. We describe a 62-year-old patient who underwent pancreaticoduodenectomy for a NEC located in the pancreatic head, with peripancreatic lymph node metastases. Tumor necrosis was prominent and the Ki67 proliferative index was 60%. One year after the diagnosis, the patient experienced recurrence with a left supraclavicular lymph node metastasis, which was surgically removed, followed by standard cisplatin-etoposide chemotherapy. Neoplastic cells showed combined loss of expression of MLH1 and PMS2 in both primary tumor and lymph node metastasis. Microsatellite instability (MSI) test using a mononucleotide repeats pentaplex PCR (BAT-25, BAT-26, NR-21, NR-22, and NR-24) revealed minimal mononucleotide shifts showing deletion of less than 3 bp at NR-21, BAT-26, NR-24, and NR-22 loci. MLH1 methylation analysis revealed absence of the gene promoter methylation. BRAF and KRAS mutations were not detected. In gut, NECs' mismatch repair deficiency phenotype has been reported in about 10% of cases, and it represents an independent factor of more favorable outcome. Likewise, our patient is currently alive with a follow-up of more than 12 years after pancreaticoduodenectomy, by itself an unexpected finding for such an aggressive neoplasm.
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http://dx.doi.org/10.1007/s12022-020-09622-5DOI Listing
December 2020

Re-irradiation With Carbon Ion Radiotherapy for Pelvic Rectal Cancer Recurrences in Patients Previously Irradiated to the Pelvis.

In Vivo 2020 May-Jun;34(3):1547-1553

National Center of Oncological Hadrontherapy (Fondazione CNAO), Pavia, Italy.

Background/aim: Re-irradiation of locally recurrent rectal cancer poses challenges due to the proximity of critical organs, such as the bowel. This study aimed at evaluating the safety and efficacy of re-irradiation with Carbon Ion Radiotherapy (CIRT) in rectal cancer patients with local recurrence.

Patients And Methods: Between 2014 and 2018, 14 patients were treated at the National Center of Oncological Hadrontherapy (CNAO Foundation) with CIRT for locally recurrent rectal cancer.

Results: All patients concluded the treatment. No G≥3 acute/late reaction nor pelvic infections were observed. The 1-year and 2-year local control rates were, 78% and 52%, respectively, and relapse occurred close to the bowel in 6 patients. The 1-year and 2-year overall survival rates were 100% and 76.2% each; while the 1-year and 2-year metastasis free survival rates were 64.3% and 43%.

Conclusion: CIRT as re-irradiation for locally recurrent rectal cancer emerges as a safe and valid treatment with an acceptable rate of morbidity of surrounding healthy tissue.
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http://dx.doi.org/10.21873/invivo.11944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279804PMC
February 2021

Comparative Study of Salivary, Duodenal, and Fecal Microbiota Composition Across Adult Celiac Disease.

J Clin Med 2020 Apr 13;9(4). Epub 2020 Apr 13.

Gastroenterology Unit, Department of Medicine, A.O.U.I. Borgo Roma and University of Verona, 37134 Verona, Italy.

Background: Growing evidence suggests that an altered microbiota composition contributes to the pathogenesis and clinical features in celiac disease (CD). We performed a comparative analysis of the gut microbiota in adulthood CD to evaluate whether: (i) dysbiosis anticipates mucosal lesions, (ii) gluten-free diet restores eubiosis, (iii) refractory CD has a peculiar microbial signature, and (iv) salivary and fecal communities overlap the mucosal one.

Methods: This is a cross-sectional study where a total of 52 CD patients, including 13 active CD, 29 treated CD, 4 refractory CD, and 6 potential CD, were enrolled in a tertiary center together with 31 controls. A 16S rRNA-based amplicon metagenomics approach was applied to determine the microbiota structure and composition of salivary, duodenal mucosa, and stool samples, followed by appropriate bioinformatic analyses.

Results: A reduction of both α- and β-diversity in CD, already evident in the potential form and achieving nadir in refractory CD, was evident. Taxonomically, mucosa displayed a significant abundance of and an expansion of , especially in active patients, while treated celiacs showed an intermediate profile between active disease and controls. The saliva community mirrored the mucosal one better than stool.

Conclusion: Expansion of pathobiontic species anticipates villous atrophy and achieves the maximal divergence from controls in refractory CD. Gluten-free diet results in incomplete recovery. The overlapping results between mucosal and salivary samples indicate the use of saliva as a diagnostic fluid.
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http://dx.doi.org/10.3390/jcm9041109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231226PMC
April 2020

Clinical phenotype and mortality in patients with idiopathic small bowel villous atrophy: a dual-centre international study.

Eur J Gastroenterol Hepatol 2020 08;32(8):938-949

Istituti Clinici Scientifici Maugeri, IRCCS, Gastroenterology Unit of Pavia Institute, University of Pavia, Pavia, Italy.

Objective: Causes of small-bowel villous atrophy (VA) include coeliac disease (CD), its complications and other rare non-coeliac enteropathies. However, forms of VA of unknown aetiology may also exist. We defined them as idiopathic VA (IVA). To retrospectively classify the largest cohort of IVA patients and compare their natural history with CD.

Methods: Notes of 76 IVA patients attending two tertiary centres between January 2000 and March 2019 were retrospectively reviewed. CD, its complications and all the known causes of VA were excluded in all of them. Persistence of VA during follow-up and lymphoproliferative features were used to retrospectively classify IVA, as follows. Group 1: IVA with spontaneous histological recovery (50 patients). Group 2: persistent IVA without lymphoproliferative features (14 patients). Group 3: persistent IVA with lymphoproliferative features (12 patients). Survival was compared between IVA groups and 1114 coeliac patients. HLA was compared between IVA patients, coeliac patients and appropriate controls.

Results: Five-year survival was 96% in IVA group 1, 100% in IVA group 2, 27% in IVA group 3 and 97% in CD. On a multivariate analysis hypoalbuminemia (P = 0.002) and age at diagnosis (P = 0.04) predicted mortality in IVA. Group 2 showed association with HLA DQB1*0301 and DQB1*06.

Conclusion: IVA consists of three groups of enteropathies with distinct clinical phenotypes and prognoses. Mortality in IVA is higher than in CD and mainly due to lymphoproliferative conditions necessitating more aggressive therapies.
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http://dx.doi.org/10.1097/MEG.0000000000001726DOI Listing
August 2020

Bilateral Breast Metastases from Epstein-Barr Virus-Associated Gastric Cancer during Pregnancy: Is There a Method to Its Madness?

J Gastric Cancer 2020 Mar 11;20(1):106-114. Epub 2019 Sep 11.

Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Breast metastases of extramammary malignant neoplasms are rare, with an incidence of 0.3%-2.7% among all malignant mammary tumors. Breast metastases from gastric carcinoma are very rare (<0.1%), and this event is even rarer during pregnancy. Herein, we describe a 39-year-old Caucasian woman with a history of an Epstein-Barr virus-associated gastric carcinoma (EBVaGC) that was characterized by prominent tumor infiltrating lymphocytes. Three years after undergoing radical surgery, the patient developed bilateral breast nodules during her pregnancy. A breast biopsy was performed, and histology confirmed a diagnosis of EBVaGC; tumor cells showed positivity for cytokeratin 8/18 and E-cadherin, and negativity for cytokeratin 7, cytokeratin 20, cytokeratin 5/6, caudal type homebox 2, androgen receptor, mammaglobin, gross cystic disease fluid protein-15, and estrogen and progesterone receptors. We also discuss the main diagnostic pitfalls. To our knowledge, this is the first report of an EBVaGC with lymphoid stroma that developed breast metastases during pregnancy.
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http://dx.doi.org/10.5230/jgc.2020.20.e1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105417PMC
March 2020

Nivolumab-associated active neutrophilic gastritis.

J Clin Pathol 2020 Sep 11;73(9):605-606. Epub 2020 Mar 11.

First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1136/jclinpath-2020-206540DOI Listing
September 2020
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