Publications by authors named "Roberto Fiocca"

86 Publications

Gastritis: update on etiological features and histological practical approach.

Pathologica 2020 Sep;112(3):153-165

Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy.

Gastric biopsies represent one of the most frequent specimens that the pathologist faces in routine activity. In the last decade or so, the landscape of gastric pathology has been changing with a significant and constant decline of -related pathologies in Western countries coupled with the expansion of iatrogenic lesions due to the use of next-generation drugs in the oncological setting. This overview will focus on the description of the elementary lesions observed in gastric biopsies and on the most recent published recommendations, guidelines and expert opinions.
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http://dx.doi.org/10.32074/1591-951X-163DOI Listing
September 2020

Non gastro-esophageal reflux disease related esophagitis: an overview with a histologic diagnostic approach.

Pathologica 2020 Sep;112(3):128-137

Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy.

Several pathological conditions, other than gastro-esophageal reflux disease and its complications, can affect the esophagus. While some of these can present with unspecific lesions (i.e. ulcers and epithelial damage) and require clinico-pathological correlation for diagnosis (i.e. drug-induced esophagitis and corrosive esophagitis) other conditions show distinctive histological lesions which enable the pathologist to reach the diagnosis (i.e. some specific infectious esophagites and Crohn's disease). In this context eosinophilic esophagitis is the condition which has been increasingly studied in the last two decades, while lymphocytic esophagitis, a relatively new entity, still represents an enigma. This overview will focus on and describe histologic lesions which allow pathologists to differentiate between these conditions.
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http://dx.doi.org/10.32074/1591-951X-156DOI Listing
September 2020

Gastro-esophageal reflux disease and Barrett's esophagus: an overview with an histologic diagnostic approach.

Pathologica 2020 Sep;112(3):117-127

Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy.

The first part of this overview on non-neoplastic esophagus is focused on gastro-esophageal reflux disease (GERD) and Barrett's esophagus. In the last 20 years much has changed in histological approach to biopsies of patients with gastro-esophageal reflux disease. In particular, elementary histologic lesions have been well defined and modality of evaluation and grade are detailed, their sensitivity and specificity has been evaluated and their use has been validated by several authors. Also if there is not a clinical indication to perform biopsies in patient with GERD, the diagnosis of microscopic esophagitis, when biopsies are provided, can be performed by following simple rules for evaluation which allow pathologists to make the diagnosis with confidence. On the other hand, biopsies are required for the diagnosis of Barrett's esophagus. This diagnosis is the synthesis of endoscopic picture (which has to be provided with the proper description on extent and with adequate biopsies number) and histologic pattern. The current guidelines and expert opinions for the correct management of these diagnosis are detailed.
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http://dx.doi.org/10.32074/1591-951X-162DOI Listing
September 2020

Targeted Sequencing of Sorted Esophageal Adenocarcinoma Cells Unveils Known and Novel Mutations in the Separated Subpopulations.

Clin Transl Gastroenterol 2020 Sep;11(9):e00202

1Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy; 2Department of Surgical and Diagnostic Sciences (DISC), University of Genova; 3Department of Pathology, IRCCS Ospedale Policlinico San Martino, Genova, Italy; 4Department of Experimental, Institute of Oncology and Transplant Pathology, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy; 5Division of Thoracic Surgery- Maria Cecilia Hospital, Cotignola, Italy; 6Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; 7Department of General Thoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland; 8Department of Gastroenterology and Hepatology, Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.

Introduction: Our study aimed at investigating tumor heterogeneity in esophageal adenocarcinoma (EAC) cells regarding clinical outcomes.

Methods: Thirty-eight surgical EAC cases who underwent gastroesophageal resection with lymph node dissection in 3 university centers were included. Archival material was analyzed via high-throughput cell sorting technology and targeted sequencing of 63 cancer-related genes. Low-pass sequencing and immunohistochemistry (IHC) were used to validate the results.

Results: Thirty-five of 38 EACs carried at least one somatic mutation that was absent in the stromal cells; 73.7%, 10.5%, and 10.5% carried mutations in tumor protein 53, cyclin dependent kinase inhibitor 2A, and SMAD family member 4, respectively. In addition, 2 novel mutations were found for hepatocyte nuclear factor-1 alpha in 2 of 38 cases. Tumor protein 53 gene abnormalities were more informative than p53 IHC. Conversely, loss of SMAD4 was more frequently noted with IHC (53%) and was associated with a higher recurrence rate (P = 0.015). Only through cell sorting we were able to detect the presence of hyperdiploid and pseudodiploid subclones in 7 EACs that exhibited different mutational loads and/or additional copy number amplifications, indicating the high genetic heterogeneity of these cancers.

Discussion: Selective cell sorting allowed the characterization of multiple molecular defects in EAC subclones that were missed in a significant number of cases when whole-tumor samples were analyzed. Therefore, this approach can reveal subtle differences in cancer cell subpopulations. Future studies are required to investigate whether these subclones are responsible for treatment response and disease recurrence.
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http://dx.doi.org/10.14309/ctg.0000000000000202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508445PMC
September 2020

Fibrotic progression and radiologic correlation in matched lung samples from COVID-19 post-mortems.

Virchows Arch 2020 Sep 28. Epub 2020 Sep 28.

Anatomic Pathology Unit, Department of Surgical Science and Integrated Diagnostics (DISC), University of Genova, Genova, Italy.

Data on the pathology of COVID-19 are scarce; available studies show diffuse alveolar damage; however, there is scarce information on the chronologic evolution of COVID-19 lung lesions. The primary aim of the study is to describe the chronology of lung pathologic changes in COVID-19 by using a post-mortem transbronchial lung cryobiopsy approach. Our secondary aim is to correlate the histologic findings with computed tomography patterns. SARS-CoV-2-positive patients, who died while intubated and mechanically ventilated, were enrolled. The procedure was performed 30 min after death, and all lung lobes sampled. Histopathologic analysis was performed on thirty-nine adequate samples from eight patients: two patients (illness duration < 14 days) showed early/exudative phase diffuse alveolar damage, while the remaining 6 patients (median illness duration-32 days) showed progressive histologic patterns (3 with mid/proliferative phase; 3 with late/fibrotic phase diffuse alveolar damage, one of which with honeycombing). Immunohistochemistry for SARS-CoV-2 nucleocapsid protein was positive predominantly in early-phase lesions. Histologic patterns and tomography categories were correlated: early/exudative phase was associated with ground-glass opacity, mid/proliferative lesions with crazy paving, while late/fibrous phase correlated with the consolidation pattern, more frequently seen in the lower/middle lobes. This study uses an innovative cryobiopsy approach for the post-mortem sampling of lung tissues from COVID-19 patients demonstrating the progression of fibrosis in time and correlation with computed tomography features. These findings may prove to be useful in the correct staging of disease, and this could have implications for treatment and patient follow-up.
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http://dx.doi.org/10.1007/s00428-020-02934-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521863PMC
September 2020

Collision Tumor Composed of an Inflammatory Myofibroblastic Tumor and Adenocarcinoma of the Colon: a Rare Entity.

J Gastrointestin Liver Dis 2020 Sep 9;29(3):461-463. Epub 2020 Sep 9.

Department of Surgery, Galliera Hospital, Genova, Italy.

This report presents the case of an 83-year old man with a collision tumor consisting of an inflammatory myofibroblastic tumor (IMT) and adenocarcinoma of the left colon. As the clinical and radiologic features of IMT are non-specific, only the accurate histopathological examination from the left hemicolectomy specimen was diagnostic. Although the prognosis of a colorectal IMT seemed more favorable than in other sites, four months after surgery the patient developed a tumor relapse. Therefore, malignant behavior of IMT could not be totally excluded. Recent studies have demonstrated that a chromosomal rearrangement involving 2p23, the site of the anaplastic lymphoma kinase (ALK) gene, is present in a subset of these tumors. In our patient, tumor cells did not present ALK-1 perinuclear positivity and it could have indicated a less favorable prognosis. The collision of these different entities is extremely rare and this is the first case reported in literature. Further cases of collision tumors with clinical information including their treatment and prognosis are needed.
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http://dx.doi.org/10.15403/jgld-782DOI Listing
September 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.

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

Transbronchial cryobiopsy: an effective tool in the diagnosis of lymphoproliferative disorders of the lung.

ERJ Open Res 2020 Jul 27;6(3). Epub 2020 Jul 27.

Dept of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy.

Introduction: Malignant lymphoproliferative disorders are rarely observed in the lung and, considering their clinical and radiological heterogeneity, diagnosis is often difficult and may require invasive methods. Transbronchial cryobiopsy has been confirmed as a new tool in the diagnosis of interstitial lung diseases, given its fewer risks and costs compared to surgical approach. This study is aimed at assessing the effectiveness of cryobiopsy in the diagnosis of lymphoproliferative disorders.

Materials And Methods: Among 970 consecutive cryobiopsies, performed between January 2011 and June 2018 at Morgagni Hospital of Forlì, Italy, 13 cases of lymphoproliferative disorders were collected.

Results: In 12 out of 13 cases a precise pathological diagnosis could be reached with the support of immunohistochemistry (IHC) and molecular ancillary studies. In the only case in which cryobiopsy did not lead to a definitive diagnosis, the subsequent surgical biopsy also did not help to clarify the diagnosis. Severe bleeding or pneumothorax did not occur in any case. On average, five biopsies were obtained per case, with a mean total area of 1161 mm, and only 5 out of 65 specimens were inadequate for diagnosis. Instant freezing did not produce tissue artefacts nor did it affect IHC and molecular tests. In all cases the amount of available tissue was sufficient for all ancillary studies.

Conclusions: Transbronchial lung cryobiopsy is safe and effective for diagnosis in patients with suspected pulmonary involvement by lymphoproliferative disorders and it should therefore be considered a valid alternative to surgical biopsy in such cases.
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http://dx.doi.org/10.1183/23120541.00260-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383053PMC
July 2020

Lung fibrosis: an undervalued finding in COVID-19 pathological series.

Lancet Infect Dis 2020 Jul 28. Epub 2020 Jul 28.

Anatomic Pathology Unit, Policlinico San Martino Hospital, Genova, Italy.

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http://dx.doi.org/10.1016/S1473-3099(20)30582-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386839PMC
July 2020

Mechanisms underlying the predictive power of high skeletal muscle uptake of FDG in amyotrophic lateral sclerosis.

EJNMMI Res 2020 Jul 7;10(1):76. Epub 2020 Jul 7.

Nuclear Medicine, IRCCS Ospedale Policlinico San Martino, Largo Benzi 10, 16132, Genova, Italy.

Background: We recently reported that enhanced [18F]-fluorodeoxyglucose (FDG) uptake in skeletal muscles predicts disease aggressiveness in patients with amyotrophic lateral sclerosis (ALS). The present experimental study aimed to assess whether this predictive potential reflects the link between FDG uptake and redox stress that has been previously reported in different tissues and disease models.

Methods: The study included 15 SOD1 mice (as experimental ALS model) and 15 wildtype mice (around 120 days old). Mice were submitted to micro-PET imaging. Enzymatic pathways and response to oxidative stress were evaluated in harvested quadriceps and hearts by biochemical, immunohistochemical, and immunofluorescence analysis. Colocalization between the endoplasmic reticulum (ER) and the fluorescent FDG analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) was performed in fresh skeletal muscle sections. Finally, mitochondrial ultrastructure and bioenergetics were evaluated in harvested quadriceps and hearts.

Results: FDG retention was significantly higher in hindlimb skeletal muscles of symptomatic SOD1 mice with respect to control ones. This difference was not explained by any acceleration in glucose degradation through glycolysis or cytosolic pentose phosphate pathway (PPP). Similarly, it was independent of inflammatory infiltration. Rather, the high FDG retention in SOD1 skeletal muscle was associated with an accelerated generation of reactive oxygen species. This redox stress selectively involved the ER and the local PPP triggered by hexose-6P-dehydrogenase. ER involvement was confirmed by the colocalization of the 2-NBDG with a vital ER tracker. The oxidative damage in transgenic skeletal muscle was associated with a severe impairment in the crosstalk between ER and mitochondria combined with alterations in mitochondrial ultrastructure and fusion/fission balance. The expected respiratory damage was confirmed by a deceleration in ATP synthesis and oxygen consumption rate. These same abnormalities were represented to a markedly lower degree in the myocardium, as a sample of non-voluntary striated muscle.

Conclusion: Skeletal muscle of SOD1 mice reproduces the increased FDG uptake observed in ALS patients. This finding reflects the selective activation of the ER-PPP in response to significant redox stress associated with alterations of mitochondrial ultrastructure, networking, and connection with the ER itself. This scenario is less severe in cardiomyocytes suggesting a relevant role for either communication with synaptic plaque or contraction dynamics.
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http://dx.doi.org/10.1186/s13550-020-00666-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340686PMC
July 2020

An Uncommon Polyp of the Right Colon: an Unusual Presentation of Melanoma.

J Gastrointest Cancer 2021 Mar;52(1):313-315

Department of Pathology, E.O. Ospedali Galliera, Genoa, Italy.

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http://dx.doi.org/10.1007/s12029-020-00430-yDOI Listing
March 2021

Correction: PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

Mod Pathol 2020 07;33(7):1453

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41379-020-0512-5DOI Listing
July 2020

PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

Mod Pathol 2020 07 17;33(7):1398-1409. Epub 2020 Feb 17.

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

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1 immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1 cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1 microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.
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http://dx.doi.org/10.1038/s41379-020-0497-0DOI Listing
July 2020

Development of a long non-coding RNA signature for prediction of response to neoadjuvant chemoradiotherapy in locally advanced rectal adenocarcinoma.

PLoS One 2020 5;15(2):e0226595. Epub 2020 Feb 5.

Department of Internal Medicine, Università degli Studi di Genova, Genova, Italy.

Standard treatment for locally advanced rectal adenocarcinoma (LARC) includes a combination of chemotherapy with pyrimidine analogues, such as capecitabine, and radiation therapy, followed by surgery. Currently no clinically useful genomic predictors of benefit from neoadjuvant chemoradiotherapy (nCRT) exist for LARC. In this study we assessed the expression of 8,127 long noncoding RNAs (lncRNAs), poorly studied in LARC, to infer their ability in classifying patients' pathological complete response (pCR). We collected and analyzed, using lncRNA-specific Agilent microarrays a consecutive series of 61 LARC cases undergoing nCRT. Potential lncRNA predictors in responders and non-responders to nCRT were identified with LASSO regression, and a model was optimized using k-fold cross-validation after selection of the three most informative lncRNA. 11 lncRNAs were differentially expressed with false discovery rate < 0.01 between responders and non-responders to NACT. We identified lnc-KLF7-1, lnc-MAB21L2-1, and LINC00324 as the most promising variable subset for classification building. Overall sensitivity and specificity were 0.91 and 0.94 respectively, with an AUC of our ROC curve = 0.93. Our study shows for the first time that lncRNAs can accurately predict response in LARC undergoing nCRT. Our three-lncRNA based signature must be independently validated and further analyses must be conducted to fully understand the biological role of the identified signature, but our results suggest lncRNAs may be an ideal biomarker for response prediction in the studied setting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226595PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001901PMC
April 2020

Comparison of pathology sampling protocols for pancreatoduodenectomy specimens.

Virchows Arch 2020 May 4;476(5):735-744. Epub 2019 Dec 4.

Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, Largo Rosanna Benzi 10, 16132, Genoa, Italy.

Pancreatoduodenectomy is one of the most challenging surgical specimens for pathologists. Recently, two different, standardized protocols have been proposed: the axial slicing Leeds protocol (LP) and the bi-valving Adsay protocol (AP). Comparison between standardized and non-standardized protocols (NSP) was performed with emphasis on margin involvement and lymph node yield. Pancreatoduodenectomy cases were retrospectively recruited: 46 sampled with LP, 52 cases with AP and 46 cases with NSP. Clinico-pathologic data and rates of margin/surface involvement were collected and their prognostic influence on survival was assessed. Statistical differences between NSP and AP and LP were seen for nodal yield (p = 0.0001), N+ (p = 0.0001) and lymph node ratio - LNR (p < 0.0008) but not between AP and LP. Differences in R1/R0 status were statistically significant between NSP group (R1-15%) and both the LP (R1-73.9%) and AP (R1-70%) groups (p = 0.0001) but not between LP and AP groups. At univariate survival analysis, grade (p = 0.0023) and number of involved margins (p = 0.0096) in AP and "N-category" (p = 0.0057) "resection margin status" (p = 0.0094), "stage" (p = 0.0143), and "number of involved margins" (p = 0.00398) in LP were statistically significant, while no variable was significant in the NSP group. At multivariate analysis "N category," "resection margin status," "stage," "number of involved margins," and "LNR" retained significance for the LP group. These results show that both LP and AP perform better than non-standardized sampling making standardization mandatory in pancreatoduodenectomy cut up. Both AP and LP show strengths and weaknesses, and these may impact on the choice of protocol in different institutions.
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http://dx.doi.org/10.1007/s00428-019-02687-6DOI Listing
May 2020

Lymph node number, surface area and lymph node ratio are important prognostic indicators in neoadjuvant chemoradiotherapy treated rectal cancer.

J Clin Pathol 2020 Mar 25;73(3):162-166. Epub 2019 Sep 25.

Department of Surgery, Ospedale Policlinico San Martino Istituto di Ricovero e Cura a Carattere Scientifico per l'Oncologia, Genova, Italy.

Aims: Neoadjuvant chemoradiotherapy (neoCRT) is recommended for locally advanced rectal cancer (RC), however, this often makes lymph node (LN) search trying. The aim of this study was to evaluate, in a large retrospective, monocentric, series of post-neoCRT-RC patients, the importance of LN number, ratio and surface area in predicting metastases, overall survival (OS) and disease free survival (DFS).

Methods: 104 patients with RC underwent total mesorectal excision, after standard neoCRT. All resected specimens were examined according to a standardised sampling/histopathological protocol. The following data regarding LNs were collected: total numbers; number with metastases; LNratio (metastatic/total); maximum diameter; surface area.

Results: A statistically significant association was found between LN number and DFS (p=0.0473). Finding ≤9 or >20 LNs correlated with worse prognosis compared with 10-20 (p value=0.049). LNratio (>0.2) was strongly associated with shorter DFS (HR=13.36; p value <0.0001) and OS (HR=26.06; p value <0.0001). Poor outcome, for DFS (HR=2.17, p value =0.0416) and OS (HR=1.18, p value =0.0025), was associated with increasing LN surface area. LNratio was independently associated with DFS at multivariate analysis (p value <0.0001).

Conclusions: LN number, LNratio and LN surface area are important prognostic factors in neoCRT-RC and in particular finding ≤9 or >20 LNs is prognostically adverse.
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http://dx.doi.org/10.1136/jclinpath-2019-206139DOI Listing
March 2020

Separation of Low- Versus High-grade Crohn's Disease-associated Small Bowel Carcinomas is Improved by Invasive Front Prognostic Marker Analysis.

J Crohns Colitis 2020 Mar;14(3):295-302

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

Background And Aims: Crohn's disease-associated small bowel carcinoma is a rare event, usually reported to have a severe prognosis. However, in previous investigations we have found a minority of cases displaying a relatively favourable behaviour, thus outlining the need to improve the histopathological prediction of Crohn's disease-associated small bowel carcinoma prognosis.

Methods: As in recent studies on colorectal cancer, a substantial improvement in prognostic evaluations has been provided by the histological analysis of the tumour invasive front; we therefore systematically analysed the tumour budding and poorly differentiated clusters in the invasive front of 47 Crohn's disease-associated small bowel carcinomas collected through the Small Bowel Cancer Italian Consortium.

Results: Both tumour budding and poorly differentiated cluster analyses proved highly effective in prognostic evaluation of Crohn's disease-associated small bowel carcinomas. In addition, they retained prognostic value when combined with two other parameters, i.e. glandular histology and stage I/II, both known to predict a relatively favourable small bowel carcinoma behaviour. In particular, association of tumour budding and poorly differentiated clusters in a combined invasive front score allowed identification of a minor subset of cancers [12/47, 25%] characterised by combined invasive front low grade coupled with a glandular histology and a low stage [I or II] and showing no cancer-related death during a median follow-up of 73.5 months.

Conclusions: The improved distinction of lower- from higher-grade Crohn's disease-associated small bowel carcinomas provided by invasive front analysis should be of potential help in choosing appropriate therapy for these rare and frequently ominous neoplasms.
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http://dx.doi.org/10.1093/ecco-jcc/jjz140DOI Listing
March 2020

Atomic force microscopy: a promising aid in diagnosis of uterine smooth muscle neoplasms.

Am J Obstet Gynecol 2019 10 20;221(4):362-364. Epub 2019 May 20.

Department of Gynecology and Obstetrics, DiNOGMI, University of Genoa, Genoa, Italy.

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http://dx.doi.org/10.1016/j.ajog.2019.05.013DOI Listing
October 2019

Clinico-pathological associations and concomitant mutations of the RAS/RAF pathway in metastatic colorectal cancer.

J Transl Med 2019 04 29;17(1):137. Epub 2019 Apr 29.

Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132, Genoa, Italy.

Background: Over the past few years, next-generation sequencing (NGS) has become reliable and cost-effective, and its use in clinical practice has become a reality. A relevant role for NGS is the prediction of response to anti-EGFR agents in metastatic colorectal cancer (mCRC), where multiple exons from KRAS, NRAS, and BRAF must be sequenced simultaneously.

Methods: We optimized a 14-amplicon NGS panel to assess, in a consecutive cohort of 219 patients affected by mCRC, the presence and clinico-pathological associations of mutations in the KRAS, NRAS, BRAF, and PIK3CA genes from formalin-fixed, paraffin-embedded specimens collected for diagnostics and research at the time of diagnosis.

Results: We observed a statistically significant association of RAS mutations with sex, young age, and tumor site. We demonstrated that concomitant mutations in the RAS/RAF pathway are not infrequent in mCRC, and as anticipated by whole-genome studies, RAS and PIK3CA tend to be concurrently mutated. We corroborated the association of BRAF mutations in right mCRC tumors with microsatellite instability. We established tumor side as prognostic parameter independently of mutational status.

Conclusions: To our knowledge, this is the first monocentric, consecutively accrued clinical mCRC cancer cohort tested by NGS in a real-world context for KRAS, NRAS, BRAF, and PIK3CA. Our study has highlighted in clinical practice findings such as the concomitance of mutations in the RAS/RAF pathway, the presence of multiple mutations in single gene, the co-occurrence of RAS and PIK3CA mutations, the prognostic value of tumor side and possible associations of sex with specific mutations.
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http://dx.doi.org/10.1186/s12967-019-1879-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489172PMC
April 2019

Abdominal Ectopic Thyroid Tissue: The Man From Istanbul.

Int J Surg Pathol 2019 Aug 14;27(5):553-555. Epub 2019 Mar 14.

1 University of Genoa, Genoa, Italy.

Thyroid ectopia is a rare finding below the diaphragm. It is characterized by normal thyroid parenchyma in unusual locations with preserved thyroid marker immunoreactivity. In this article, we present the first known case of thyroid tissue in the periappendiceal fat and discuss possible ethiopathogenic theories.
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http://dx.doi.org/10.1177/1066896919833784DOI Listing
August 2019

Agar pre-embedding of small skin biopsies: real-life benefits and challenges in high throughput pathology laboratories.

J Clin Pathol 2019 Jun 20;72(6):448-451. Epub 2019 Feb 20.

Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), Univeristy of Genoa, Genoa, Italy

Paraffin embedding of small, thin tissue samples requires specific expertise for optimal orientation before tissue sectioning. This study evaluates the real-life utility of the agar pre-embedding technique for small skin biopsies with regards to lengthening of work times, problems in orientation (re-embedding) and ancillary techniques (immunohistochemistry and in situ hybridisation) between two high work flow pathology laboratories, one of which routinely uses the agar pre-embedding technique and one which does not. The mean time required for pre-embedding in agar was 30.4 s, but time for paraffin embedding for agar pre-embedded samples was shorter than the traditional method (177 vs 296 s; p<0.005). The number of skin samples requiring re-embedding was significantly higher with the traditional embedding method (p<0.005). No problems in immunoreactivity were observed in all 1900 reactions performed with 17 different antibodies. Fluorescence in situ hybridisation analysis was optimised with a prolonged protease K incubation time (21 vs 18 min).
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http://dx.doi.org/10.1136/jclinpath-2018-205680DOI Listing
June 2019

Coping with formalin banning in pathology: under vacuum long-term tissue storage with no added formalin.

Histochem Cell Biol 2019 Jun 2;151(6):501-511. Epub 2019 Jan 2.

Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, via De Toni 14, 16132, Genoa, Italy.

Formalin is toxic and has recently been classified as carcinogenic leading to a proposed European formalin ban. But, the pathology use of formalin has however been completely overlooked, and this is proving to be a relevant issue, as no alternative, reliable, tissue fixative is available. Various systems have been proposed to reduce formalin use and exposure; long-term storage and disposal of formalin is also a problem. With this in mind, under vacuum sealing (UVS) systems have been proposed for transportation/storage, however, for how long tissue retains its characteristics (morphological and molecular) is unknown. This study aims to compare histology specimens stored by formalin immersion (FI) and specimens stored after fixation with UVS technique with no additional formalin, at different time periods. Twenty tissue samples (10FI; 10UVS) were stored for different time periods (15 days, 1-2-3-6-12 months) for a total of 120 samples, compared with regard to their morphology, histochemistry, immunoreactivity (24 specific antibodies) and DNA status. All samples showed well-preserved morphology and overlapping staining quality. A significant reduction in immunoreactivity was however identified in the various time periods, particularly for heat pre-treated nuclear antigens, and this commenced earlier (1 month) for FI. UVS storage showed higher DNA content than FI but slightly poorer DNA integrity. These results add important knowledge to the use of UVS in daily practice, as long-term storage of pre-fixed tissue in UVS is not detrimental to the quality of tissue while having the boon of using very little formalin with less operator exposure and lower disposal costs.
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http://dx.doi.org/10.1007/s00418-018-1765-7DOI Listing
June 2019

Pneumomediastinum after transbronchial cryobiopsy.

Monaldi Arch Chest Dis 2018 Jun 22;88(2):909. Epub 2018 Jun 22.

IRCCS Ospedale Policlinico San Martino, University of Genoa, Pulmonology Division.

Pneumomediastinum is defined as the presence of air or gas within the mediastinum and it rarely complicates bronchoscopy. We report, to our best knowledge, the first case of pneumomediastinum following a transbronchial cryobiopsy (TBLC). TBLC is considered a safe procedure as compared with both transbronchial biopsy and surgical lung biopsy. Systematic reviews, metanalysis and a Pubmed research, revealed that in literature no pneumomediastinum has been mentioned after TBLC. We report this case for to make it known to interventional pulmonologists the possibility that a pneumomediastinum can follow a TBLC. In our case the spontaneous resolution in few days did not require any intervention.
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http://dx.doi.org/10.4081/monaldi.2018.909DOI Listing
June 2018

Clinical and pharmacogenetic determinants of 5-fluorouracyl/leucovorin/irinotecan toxicity: Results of the PETACC-3 trial.

Eur J Cancer 2018 08 14;99:66-77. Epub 2018 Jun 14.

Digestive Tumors Unit, Geneva University Hospital, Geneva, Switzerland.

Purpose: Irinotecan (CPT-11) in combination with 5-fluorouracil (5FU) is widely used in the treatment of colorectal cancer. We assessed potential clinical variables that may predict toxicity and more specifically the role of UGT1A1 polymorphisms associated with irinotecan toxicity. We used data from the PETACC3 trial, which randomised patients in adjuvant setting to 6 months of leucovorin (LV) and 5FU (LV5/FU2) or LV5/FU2 + irinotecan.

Patients And Methods: Clinical and toxicity data were available for 2982 patients, DNA was available for 1200 (40%) of these patients. We genotyped the polymorphisms UGT1A1*28 and UGT1A1-3156G > A. Risk factors for neutropenia and diarrhoea were assessed by univariable and multivariable analyses.

Results: In univariable analysis, UGT1A*28 genotype was associated with an increased incidence of grade III-IV neutropenia (incidence: 44% versus 26%; odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.4-3.7). In multivariable analysis, the most important predictors (ordered in terms of contribution to R) were baseline neutrophil count (OR for 1-unit (10/l) decrease: 1.8, 95% CI: 1.3-1.7), female sex (OR: 1.8, 95% CI: 1.1-3.0), body surface area (OR for 0.1-unit increase: 0.8, 95% CI: 0.7-1.0), UGT1A1 (OR: 2.8, 95% CI: 1.6-5.0), age (OR per 10 years: 1.3, 95% CI: 1.1-1.6) and poor performance status (OR: 1.6, 95% CI: 1.0-2.6). The main predictors for grade IV neutropenia were sex, age, performance score and UGT1A1. The main predictors for diarrhoea were sex and age.

Conclusions: We found that a complex of risk factors is involved in the development of toxicity, including UGT1A1. Parameters that are readily available in clinical practice, notably sex, age and performance status, are stronger predictors than the UGT1A1*28 genotype. Further studies beyond the UGT1A1*28 genotype are needed to fully understand the determinants of toxicity risk, notably in females.
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http://dx.doi.org/10.1016/j.ejca.2018.05.009DOI Listing
August 2018

HLA-G expression in gastric carcinoma: clinicopathological correlations and prognostic impact.

Virchows Arch 2018 Oct 29;473(4):425-433. Epub 2018 May 29.

Anatomic Pathology Unit, Department of Surgical and Diagnostic Sciences, University of Genoa and Ospedale Policlinico San Martino, Genoa, Italy.

To analyze expression of human leukocyte antigen-G (HLA-G) in gastric adenocarcinoma and correlate its expression with histological and clinical variables. A continuous series of 94 unselected patients with gastric adenocarcinoma (stage I to III) were selected. All histological and clinical variables were collected including the intensity of intra- and peri-tumor lymphocytic infiltration. HLA-G expression was investigated using immunohistochemistry. All histological samples analyzed for HLA-G expression were taken from the primary gastric lesion and included non-neoplastic mucosa. Evaluation of HLA-G expression was performed on the transition zone between tumor and non-neoplastic mucosa, and the invasive front of the tumor and assessment was performed as follows: percentage of positive (strong expression vs weak) cells. A variable amount of HLA-G-positive tumor cells was found in 24 out of 94 cases (25.5%). No significant correlation was found between HLA-G expression and other clinicopathological variables (sex, age, stage, grade, histotype). The overall median survival was worse in patients with HLA-G-positive adenocarcinoma (24.3 months, CI 7.7-41.0) compared to those with HLA-G-negative tumors (66.3 months, CI 53.0-79.7; p < 0.0001). Two- and 5-year survival rates of HLA-G-negative patients were 88 and 44%, respectively, while were 42 and 11% in those HLA-G-positive. This trend was observed in all stages but was more marked in stage III. HLA-G expression is associated with poor survival in stage III gastric cancer patients and represents a possible immunoescape mechanism of cancer cells.
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http://dx.doi.org/10.1007/s00428-018-2379-0DOI Listing
October 2018

Kidney Ultrastructure by Atomic Force Microscopy Imaging Directly From Formalin Fixed-Paraffin Embedded Biopsy: Is This a Dream Come True?

Int J Surg Pathol 2018 09 26;26(6):532-533. Epub 2017 Dec 26.

1 University of Genoa, Genoa, Italy.

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http://dx.doi.org/10.1177/1066896917749930DOI Listing
September 2018

Natural history of Helicobacter pylori VacA toxin in human gastric epithelium in vivo: vacuoles and beyond.

Sci Rep 2017 11 6;7(1):14526. Epub 2017 Nov 6.

Department of Molecular Medicine, Pathologic Anatomy and Human Physiology Units, University of Pavia, Pavia, Italy.

Uptake, intracellular trafficking and pathologic effects of VacA toxin from Helicobacter pylori have been widely investigated in vitro. However, no systematic analysis investigated VacA intracellular distribution and fate in H. pylori-infected human gastric epithelium in vivo, using ultrastructural immunocytochemistry that combines precise toxin localization with analysis of the overall cell ultrastructure and intercompartimental/interorganellar relationships. By immunogold procedure, in this study we investigated gastric biopsies taken from dyspeptic patients to characterize the overall toxin's journey inside human gastric epithelial cells in vivo. Endocytic pits were found to take up VacA at sites of bacterial adhesion, leading to a population of peripheral endosomes, which in deeper (juxtanuclear) cytoplasm enlarged and fused each other to form large VacA-containing vacuoles (VCVs). These directly opened into endoplasmic reticulum (ER) cisternae, which in turn enveloped mitochondria and contacted the Golgi apparatus. In all such organelles we found toxin molecules, often coupled with structural damage. These findings suggest direct toxin transfer from VCVs to other target organelles such as ER/Golgi and mitochondria. VacA-induced cytotoxic changes were associated with the appearance of auto(phago)lysosomes containing VacA, polyubiquitinated proteins, p62/SQSTM1 protein, cathepsin D, damaged mitochondria and bacterial remnants, thus leading to persistent cell accumulation of degradative products.
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http://dx.doi.org/10.1038/s41598-017-15204-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673961PMC
November 2017

Diagnosis and Endoscopic Management of Barrett's Esophagus: an Italian Experts' Opinion based document.

Dig Liver Dis 2017 Dec 1;49(12):1306-1313. Epub 2017 Sep 1.

Pathology Section, Department of Molecular and Translational Medicine, Spedali Civili and University of Brescia, Brescia, Italy.

Background: Barrett's esophagus (BE) is recognized as a risk factor for esophageal adenocarcinoma. An expert panel was organized in Italy with the aim of drafting a series of statements on BE to guide diagnosis and management of patients with BE.

Methods: The working Group Coordinators worked on a literature search to identify key topics regarding critical steps of the endoscopic approach to BE. Based on the search and their expert opinion, a list of most meaningful questions was prepared and emailed to all members who were asked to vote the questions. When the survey was completed a consensus meeting was organized. According to the survey results, Group Coordinators proposed a draft statement that was voted. By definition, the statement was formulated when there was an agreement of ≥50% among participants.

Results: Twenty nine participants deliberated 18 questions. The agreement was reached for 16 questions for which a recommendation was formulated.

Conclusion: The generated statements highlight the Italian contribution to the European Position Statement of the European Society of Gastrointestinal Endoscopy. The Italian statements preserve peculiarities when dealing with the endoscopic management of BE and wishes to be considered as a contribution for the care of BE patients even with a low risk of progression to esophageal neoplasia.
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http://dx.doi.org/10.1016/j.dld.2017.08.034DOI Listing
December 2017

Erratum to: KI-67 heterogeneity in well differentiated gastro-entero-pancreatic neuroendocrine tumors: when is biopsy reliable for grade assessment?

Endocrine 2017 09;57(3):503

Pathology Unit, Department of Surgical Science and Integrated Diagnostics (DISC), University of Genoa, Largo Rosanna Benzi, 10, Genoa, 16132, Italy.

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http://dx.doi.org/10.1007/s12020-017-1389-zDOI Listing
September 2017

KI-67 heterogeneity in well differentiated gastro-entero-pancreatic neuroendocrine tumors: when is biopsy reliable for grade assessment?

Endocrine 2017 Sep 19;57(3):494-502. Epub 2017 Jul 19.

Pathology Unit, Department of Surgical Science and Integrated Diagnostics (DISC), University of Genoa, Largo Rosanna Benzi, 10, Genoa, 16132, Italy.

Purpose: Ki-67 heterogeneity can impact on gastroenteropancreatic neuroendocrine tumor grade assignment, especially when tissue is scarce. This work is aimed at devising adequacy criteria for grade assessment in biopsy specimens.

Method: To analyze the impact of biopsy size on reliability, 360 virtual biopsies of different thickness and lengths were constructed. Furthermore, to estimate the mean amount of non-neoplastic tissue component present in biopsies, 28 real biopsies were collected, the non-neoplastic components (fibrosis and inflammation) quantified and the effective area of neoplastic tissue calculated for each biopsy.

Results: Heterogeneity of Ki-67 distribution, G2 tumors and biopsy size all play an important role in reducing the reliability of biopsy samples in Ki-67-based grade assignment. In particular in G2 cases, 59.9% of virtual biopsies downgraded the tumor and the smaller the biopsy, the more frequent downgrading occurs. In real biopsies the presence of non-neoplastic tissue reduced the available total area by a mean of 20%.

Conclusions: By coupling the results from these two different approaches we show that both biopsy size and non-neoplastic component must be taken into account for biopsy adequacy. In particular, we can speculate that if the minimum biopsy area, necessary to confidently (80% concordance) grade gastro-entero-pancreatic neuroendocrine tumors on virtual biopsies ranges between 15 and 30 mm, and if real biopsies are on average composed of only 80% of neoplastic tissue, then biopsies with a surface area not <12 mm should be performed; using 18G needles, this corresponds to a minimum total length of 15 mm.
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http://dx.doi.org/10.1007/s12020-017-1364-8DOI Listing
September 2017