Publications by authors named "Stefano Ascani"

153 Publications

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 2: Subtypes and Divergent Differentiation.

Int J Mol Sci 2022 Jul 16;23(14). Epub 2022 Jul 16.

Department of Urology and Renal Transplantation, Policlinico Riuniti, University of Foggia, 71122 Foggia, Italy.

Following several attempts to achieve a molecular stratification of bladder cancer (BC) over the last decade, a "consensus" classification has been recently developed to provide a common base for the molecular classification of bladder cancer (BC), encompassing a six-cluster scheme with distinct prognostic and predictive characteristics. In order to implement molecular subtyping (MS) as a risk stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The second part of this review deals with the pathological and clinical features of the molecular clusters, both in conventional and divergent urothelial carcinoma, with a focus on the role of IHC-based subtyping.
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http://dx.doi.org/10.3390/ijms23147844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317362PMC
July 2022

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 1: General Issues and Marker Expression.

Int J Mol Sci 2022 Jul 15;23(14). Epub 2022 Jul 15.

Department of Urology and Renal Transplantation, Policlinico Riuniti, University of Foggia, 71122 Foggia, Italy.

Bladder cancer (BC) is a heterogeneous disease with highly variable clinical and pathological features, and resulting in different outcomes. Such heterogeneity ensues from distinct pathogenetic mechanisms and may consistently affect treatment responses in single patients. Thus, over the last few years, several groups have developed molecular classification schemes for BC, mainly based on their mRNA expression profiles. A "consensus" classification has recently been proposed to combine the published systems, agreeing on a six-cluster scheme with distinct prognostic and predictive features. In order to implement molecular subtyping as a risk-stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The first part of this review deals with the steps resulting in the development of a molecular subtyping of BC, its prognostic and predictive implications, and the main features of immunohistochemical markers used as surrogates to stratify BC into pre-defined molecular clusters.
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http://dx.doi.org/10.3390/ijms23147819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319819PMC
July 2022

Robotic versus Laparoscopic Gastrectomy for Gastric Cancer: An Updated Systematic Review.

Medicina (Kaunas) 2022 Jun 20;58(6). Epub 2022 Jun 20.

Surgical Oncology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

: Gastrectomy with D2 lymphadenectomy is the standard surgical treatment with curative intent for patients with gastric cancer (GC). Over the last three decades, surgeons have been increasingly adopting laparoscopic surgery for GC, due to its better short-term outcomes. In particular, laparoscopic gastrectomy (LG) has been routinely used for early gastric cancer (EGC) treatment. However, LG suffers from technical limitations and drawbacks, such as a two-dimensional surgical field of view, limited movement of laparoscopic tools, unavoidable physiological tremors and discomfort for operating surgeon. Therefore, robotic surgery has been developed to address such limitations. : We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines in order to investigate the benefits and harms of robotic gastrectomy (RG) compared to the LG. PubMed/MEDLINE, Scopus, Cochrane Library (Cochrane Database of Systematic Re-views, Cochrane Central Register of Controlled Trials-CENTRAL) and Web of Science (Science and Social Science Citation Index) databases were used to search all related literature. : The 7 included meta-analyses covered an approximately 20 years-study period (2000-2020). Almost all studies included in the meta-analyses were retrospective ones and originated from Asian countries (China and Korea, in particular). Examined overall population ranged from 3176 to 17,712 patients. If compared to LG, RG showed both operative advantages (operative time, estimated blood loss, number of retrieved lymph nodes) and perioperative ones (time to first flatus, time to restart oral intake, length of hospitalization, overall complications, Clavien-Dindo (CD) ≥ III complications, pancreatic complications), in the absence of clear differences of oncological outcomes. However, costs of robotic approach appear significant. : It is impossible to make strong recommendations, due to the statistical weakness of the included studies. Further randomized, possibly multicenter trials are strongly recommended, if we want to have our results confirmed.
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http://dx.doi.org/10.3390/medicina58060834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9231199PMC
June 2022

Continuous suturing in hepaticojejunostomy after pancreaticoduodenectomy/total pancreatectomy: a risk factor for biliary leaks or strictures?

HPB (Oxford) 2022 May 30. Epub 2022 May 30.

Surgical Oncology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

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http://dx.doi.org/10.1016/j.hpb.2022.05.1343DOI Listing
May 2022

Cutaneous Involvement in Diseases with Plasma Cell Differentiation: Diagnostic Approach.

Curr Oncol 2022 04 24;29(5):3026-3043. Epub 2022 Apr 24.

Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy.

Neoplasms with plasma cell differentiation may occasionally involve the skin. Cutaneous lesions may represent the first sign of an underlying systemic plasma cell malignancy, such as multiple myeloma, or the skin itself may be the primary site of occurrence of a hematological tumor with plasma cell differentiation. Starting from examples encountered in our daily practice, we discussed the diagnostic approach pathologists and clinicians should use when faced with cutaneous lesions with plasma cell differentiation. Cases of primary cutaneous marginal zone lymphoma, localized primary amyloidosis/amyloidoma, and cutaneous manifestations (secondary either to multiple myeloma or to plasmablastic lymphoma) are discussed, focusing on the importance of the adequate patient's work-up and precise clinicopathological correlation to get to the correct diagnosis and appropriate treatment. The pertinent literature has been reviewed, and the clinical presentation, pathological findings, main differential diagnoses, treatment, and outcome of neoplasms with plasma cell differentiation involving the skin are discussed.
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http://dx.doi.org/10.3390/curroncol29050246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9139249PMC
April 2022

When idiopathic retroperitoneal fibrosis mimics Castleman disease: a challenging differential diagnosis.

BMJ Case Rep 2022 04 7;15(4). Epub 2022 Apr 7.

Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, Terni, Italy.

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http://dx.doi.org/10.1136/bcr-2021-248051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990696PMC
April 2022

Looking for a Simplified Diagnostic Model to Identify Potentially Lethal Cases of Prostate Cancer at Initial Diagnosis: An ImGO Pilot Study.

Cancers (Basel) 2022 Mar 17;14(6). Epub 2022 Mar 17.

Medical and Translational Oncology Unit, Department of Oncology, Azienda Ospedaliera Santa Maria, 05100 Terni, Italy.

The recurrent genetic anomalies used to classify prostate cancer (PC) into distinct molecular subtypes have limited relevance for clinical practice. In consideration of WHO 2016 histological classification, which includes the introduction of Gleason Score 4 for patients with cribriform component and the definition of intraductal carcinoma as a new entity, a retrospective pilot study was conducted to investigate, by histological review, if there were any variations of Gleason Score and the incidence of intraductal carcinoma and cribriform pattern, intended as "phenotypic" markers of potentially lethal PC, among metastatic castration-sensitive PC (mCSPC) and metastatic castration-resistant PC (mCRPC) samples. Potentially predictive factors were also assessed. Among 125 cases, a variation in the Gleason Score was reported in 26% of cases. A cribriform (36%) or intraductal (2%) pattern was reported in a higher percentage. Of them, a primary Gleason pattern 4 was reported in 80% of cases. All patients with intraductal carcinoma present a mutation, also found in 80% of cases with a cribriform pattern. This pilot study documented some hypothesis-generating data, as the evaluation of de novo mCSPC and mCRPC as phenotypic/biologic model to be translated in clinical practice. A cribriform pattern/intraductal carcinoma might be a marker of potentially lethal PC. The high incidence of and mutations in de novo mCSPC may also have a therapeutic implication.
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http://dx.doi.org/10.3390/cancers14061542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946832PMC
March 2022

Visceral Leishmaniasis Associated with B-Cell Chronic Lymphocytic Leukemia: Report of a Case and Review of the Literature.

Life (Basel) 2022 Jan 27;12(2). Epub 2022 Jan 27.

Pathology Unit, Azienda Ospedaliera "Santa Maria" di Terni, University of Perugia, 05100 Terni, Italy.

Infections often complicate the course of hematological diseases and may represent a diagnostic challenge. In particular, visceral leishmaniasis diagnosis may be missed in lymphoma patients, as lymphoma-related immunosuppression can lead to a misleadingly negative serology and to atypical clinical manifestations, including the lack of fever, considered a common symptom in leishmaniasis. Herein, we report a case of visceral leishmaniasis in a patient with a long history of B-cell chronic lymphocytic leukemia presenting with increasing fatigue and diarrhea, in the absence of fever. serology was negative. Bone marrow biopsy performed with the clinical suspicion of transformation to high-grade lymphoma disclosed intracytoplasmic inclusion bodies resembling within the cytoplasm of macrophages, and CD1a immunohistochemical expression helped to confirm the diagnosis of leishmaniasis. Liposomal amphotericin B was administered with complete symptom resolution. The correct identification of is critical as visceral leishmaniasis represents a severe disease with an often fatal outcome, particularly in frail patients, unless promptly recognized and adequately treated. A review of the literature of visceral leishmaniasis cases occurring in B-cell chronic lymphocytic leukemia patients is performed.
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http://dx.doi.org/10.3390/life12020185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8880775PMC
January 2022

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, , , and Other Genes.

Biomedicines 2022 Jan 22;10(2). Epub 2022 Jan 22.

Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

Pembrolizumab (anti-PD-1) is allowed in selected metastatic castration-resistant prostate cancer (PC) patients showing microsatellite instability/mismatch repair system deficiency (MSI-H/dMMR). loss-of-function is linked to hereditary PCs and homologous recombination DNA-repair system deficiency: poly-ADP-ribose-polymerase inhibitors can be administered to -mutated PC patients. Recently, docetaxel-refractory metastatic castration-resistant PC patients with or somatic mutations had higher response rates to pembrolizumab. regulates cell cycle/proliferation/apoptosis through pathways including the AKT/mTOR, which upregulates PD-L1 expression in PC. Our systematic literature review (PRISMA guidelines) investigated the potential correlations between PD-L1 and MMR/MSI/ statuses in PC, discussing few other relevant genes. Excluding selection biases, 74/677 (11%) PCs showed dMMR/MSI; 8/67 (12%) of dMMR/MSI cases were PD-L1+. dMMR-PCs included ductal (3%) and acinar (14%) PCs (all cases tested for MSI were acinar-PCs). In total, 15/39 (39%) PCs harbored aberrations: limited data are available for PD-L1 expression in these patients. 13/137 (10%) PTEN- PCs were PD-L1+; 10/29 (35%) PD-L1+ PCs showed PTEN negativity. mutations may increase PD-L1 levels, while the potential correlation between PD-L1 and ERG expression in PC should be clarified. Further research should verify how the efficacy of PD-1 inhibitors in metastatic castration-resistant PCs is related to dMMR/MSI, DNA-damage repair genes defects, or PD-L1 expression.
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http://dx.doi.org/10.3390/biomedicines10020236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8868626PMC
January 2022

Primary Diffuse Large B-Cell Lymphoma of the Urinary Bladder: Update on a Rare Disease and Potential Diagnostic Pitfalls.

Curr Oncol 2022 02 10;29(2):956-968. Epub 2022 Feb 10.

Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy.

Diffuse large B-cell lymphoma (DLBCL) represents the most frequent type of non-Hodgkin lymphoma. Globally, DLBCL is an aggressive disease, requiring an accurate diagnosis and prompt treatment. The diagnosis is often made on biopsy samples of a nodal mass, however, approximately 40% of DLBCL cases arise at extranodal sites. The most common extranodal site is the gastrointestinal tract, however any extranodal area may be primarily involved. Primary urinary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas, whereas secondary involvement of the urinary bladder by a systemic lymphoma is a more common event. Despite being rare, DLBCL is considered to represent the predominant primary urinary bladder lymphoma. The majority of cases reported in the bladder belong to the DLBCL, NOS group, and there are only rare cases of EBV-positive DLBCL, NOS. In this review, we summarize the current knowledge on DLBCL primarily occurring in the urinary bladder, with the aim of increasing clinician and pathologist awareness on this aggressive lymphoma rarely arising in the urinary bladder. Additionally, we focus on those entities which should be taken into consideration in the differential diagnosis, highlighting potential diagnostic pitfalls.
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http://dx.doi.org/10.3390/curroncol29020081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870454PMC
February 2022

Nectin-4 and DNA mismatch repair proteins expression in upper urinary tract urothelial carcinoma (UTUC) as a model for tumor targeting approaches: an ImGO pilot study.

BMC Cancer 2022 Feb 14;22(1):168. Epub 2022 Feb 14.

Medical and Translational Oncology Unit, Department of Oncology, Azienda Ospedaliera Santa Maria, Terni, Italy.

Background: Upper urinary tract urothelial carcinoma (UTUC) accounts for only about 5-10% of all urothelial cancers and is characterized by an aggressive and frequently rapidly fatal behavior. However, detailed knowledge of its molecular profile is still lacking.

Materials And Methods: We identified, by chart analysis, patients who underwent radical nephroureterectomy or diagnostic biopsy for UTUC between January 2015 and August 2020 at the Santa Maria Hospital of Terni, in Italy. Eligible patients were required to have also adequate clinical informations and follow-up details. The primary objective of the study was to evaluate DNA mismatch repair (MMR) proteins and Nectin-4 immunohistochemical expression in UTUC, looking also for an eventual correlation between these molecular features. The secondary objective was to investigate genomic instability in the case of a MMR protein loss. Expression of proteins was assessed by using immunohistochemistry and microsatellite instability (MSI) performed by next generation sequencing. Nectin-4 expression was reported using an intensity scoring system (score, 0-3+), instead the expression of DNA MMR proteins was indicated as present (no loss) or not present (loss).

Results: Thirty four cases have been evaluated and 27 considered eligible for the study with their tumor samples analyzed. Nectin-4 was found to be expressed in 44% of cases and 18.5% of patients showed defective-MMR phenotype. We found a significant correlation between Nectin-4 expression and MSH2/MSH6 protein loss. Out of 7 patients with DNA MMR proteins loss or equivocal phenotype, 3 showed MSI.

Conclusions: Our pilot study suggest a possible relationship between Nectin-4 and DNA MMR protein expression in UTUC and a clinically significant correlation between defective MMR phenotype and genomic instability. Because of the possible implications of these data for innovative treatment approaches, the need for further studies in this area is warranted.
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http://dx.doi.org/10.1186/s12885-022-09259-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8845253PMC
February 2022

Long-Term Outcomes of Surgical Resection of Pathologically Confirmed Isolated Para-Aortic Lymph Node Metastases in Colorectal Cancer: A Systematic Review.

Cancers (Basel) 2022 Jan 28;14(3). Epub 2022 Jan 28.

Surgical Oncology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

Background: Para-aortic lymph node (PALN) metastases represent patterns of initial recurrence in only 2-6% CRC patients, after an estimated 23-28 month time interval. An increasing trend towards curative surgery has been witnessed in patients presenting with controlled PALN recurrence. Nevertheless, lack of consensus has impaired an unambiguous statement for PALN recurrence resection.

Methods: We performed a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines, which led us to gain deeper insight into the prognostic factors and long-term outcomes after resection for synchronous or metachronous pathologically confirmed CRC isolated para-aortic lymph node metastases (PALNM). Pubmed/MEDLINE, Embase, Scopus, Cochrane Library and Web of Science databases were used to search all related literature.

Results: The nine articles included covered a study period of 30 years (1988-2018), with a total of 161 patients. At presentation, most primary CRCs were located in the colon (74%) and 95.6%, 87.1% and 76.9% patients had T3-T4, N1-N2 and well/moderately differentiated CRC, respectively. We identified a 59.4-68% 3-year OS rate and 53.4-87.5% 5-year OS rate, with a 25-84 months median OS, 26.3-61% 3-year DFS rate and 0-60.5% 5-year DFS rate, with a 14-24 month median DFS. Overall, 62.1% re-recurrence rate ranged from 43.8% to 100%.

Conclusions: Although PALNMs resection in CRC patients may be considered a feasible and beneficial option, no conclusions or recommendations can be made taking into account the current evidence. Therefore, further randomized, possibly multicenter trials are strongly recommended and mandatory if we want to have our results confirmed and patient selection criteria clearly identified.
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http://dx.doi.org/10.3390/cancers14030661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833834PMC
January 2022

The classification of neuroendocrine neoplasms of the lung and digestive system according to WHO, 5th edition: similarities, differences, challenges, and unmet needs.

Panminerva Med 2022 Jun 11;64(2):259-264. Epub 2022 Feb 11.

Institute of Thoracic Surgery, University of Foggia, Foggia, Italy.

Neuroendocrine neoplasms (NENs) are a group of disease entities sharing common morphological, ultrastructural and immunophenotypical features, yet with distinct biological behavior and clinical outcome, ranging from benign to frankly malignant. Accordingly, a spectrum of therapeutic options for each single entity is available, including somatostatin analogues (SSA), mTOR-inhibitors, peptide receptor radionuclide therapy (PRRT), non-platinum and platinum chemotherapy. In the last few decades, several attempts have been made to better stratify these lesions refining the pathological classifications, so as to obtain an optimal correspondence between the scientific terminology and, the predictive and prognostic features of each disease subtype, and achieve a global Classification encompassing NENs arising at different anatomical sites. The aim of this review was to analyze, compare and discuss the main features and issues of the latest WHO Classifications of NENs of the lung and the digestive system, in order to point out the strengths and limitations of our current understanding of these complex diseases.
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http://dx.doi.org/10.23736/S0031-0808.22.04602-XDOI Listing
June 2022

High grade B-cell lymphoma with , and/or rearrangements: unraveling the genetic landscape of a rare aggressive subtype of non-Hodgkin lymphoma.

Leuk Lymphoma 2022 06 19;63(6):1356-1362. Epub 2022 Jan 19.

Hematology and Bone Marrow Transplantation Unit, University of Perugia, Perugia, Italy.

High-grade B-cell lymphoma with and and/or rearrangements (DH/TH-HGBL) still miss an in-depth genomic characterization. To identify accompanying genetic events, we performed a pilot study on 7 cases by applying DNA microarray and targeted NGS sequencing. Interestingly, the genetic background of DH/TH-HGBL is largely overlapping with that of other high-grade/poor prognosis lymphomas. Namely, copy number abnormalities were trisomy of chromosome 7 and chromosome 8q gain, encompassing . Among gene variants, those affecting transcription factors (), epigenetic modulators (, and ), and anti-apoptotic gene (), were recurrent. and were mutated in 3 and 5 cases, respectively. In addition, mutations of previously reported in Diffuse Large B-Cell Lymphomas, were also detected. Clarifying the genomic background of this subset of high-risk lymphomas will pave the way for the clinical use of new biomarkers to: (1) monitor treatment response and; (2) consider alternative targeted therapies.
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http://dx.doi.org/10.1080/10428194.2021.2024821DOI Listing
June 2022

Surgical resection versus radiofrequency ablation for the curative treatment of intrahepatic recurrent hepatocellular carcinoma: an unsolved question.

HPB (Oxford) 2022 Jun 20;24(6):994-995. Epub 2021 Dec 20.

Pathology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

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http://dx.doi.org/10.1016/j.hpb.2021.12.011DOI Listing
June 2022

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 7: PD-L1 Expression in Liquid Biopsy.

J Pers Med 2021 Dec 6;11(12). Epub 2021 Dec 6.

Fertility Center, Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

Liquid biopsy is an accessible, non-invasive diagnostic tool for advanced prostate cancer (PC) patients, potentially representing a real-time monitoring test for tumor evolution and response to treatment through the analysis of circulating tumor cells (CTCs) and exosomes. We performed a systematic literature review (PRISMA guidelines) to describe the current knowledge about PD-L1 expression in liquid biopsies of PC patients: 101/159 (64%) cases revealed a variable number of PD-L1+ CTCs. Outcome correlations should be investigated in larger series. Nuclear PD-L1 expression by CTCs was occasionally associated with worse prognosis. Treatment (abiraterone, enzalutamide, radiotherapy, checkpoint-inhibitors) influenced PD-L1+ CTC levels. Discordance in PD-L1 status was detected between primary vs. metastatic PC tissue biopsies and CTCs vs. corresponding tumor tissues. PD-L1 is also released by PC cells through soluble exosomes, which could inhibit the T cell function, causing immune evasion. PD-L1+ PC-CTC monitoring and genomic profiling may better characterize the ongoing aggressive PC forms compared to PD-L1 evaluation on primary tumor biopsies/prostatectomy specimens (sometimes sampled a long time before recurrence/progression). Myeloid-derived suppressor cells and dendritic cells (DCs), which may have immune-suppressive effects in tumor microenvironment, have been found in PC patients circulation, sometimes expressing PD-L1. Occasionally, their levels correlated to clinical outcome. Enzalutamide-progressing castration-resistant PC patients revealed increased PD-1+ T cells and circulating PD-L1/2+ DCs.
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http://dx.doi.org/10.3390/jpm11121312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8709072PMC
December 2021

EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 3).

Cancers (Basel) 2021 Nov 30;13(23). Epub 2021 Nov 30.

Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy.

EBV is the first known oncogenic virus involved in the development of several tumors. The majority of the global population are infected with the virus early in life and the virus persists throughout life, in a latent stage, and usually within B lymphocytes. Despite the worldwide diffusion of EBV infection, EBV-associated diseases develop in only in a small subset of individuals often when conditions of immunosuppression disrupt the balance between the infection and host immune system. EBV-driven lymphoid proliferations are either of B-cell or T/NK-cell origin, and range from disorders with an indolent behavior to aggressive lymphomas. In this review, which is divided in three parts, we provide an update of EBV-associated lymphoid disorders developing in the gastrointestinal tract, often representing a challenging diagnostic and therapeutic issue. Our aim is to provide a practical diagnostic approach to clinicians and pathologists who face this complex spectrum of disorders in their daily practice. In this part of the review, the chronic active EBV infection of T-cell and NK-cell type, its systemic form; extranodal NK/T-cell lymphoma, nasal type and post-transplant lymphoproliferative disorders are discussed.
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http://dx.doi.org/10.3390/cancers13236021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656853PMC
November 2021

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 1: Focus on Immunohistochemical Results with Discussion of Pre-Analytical and Interpretation Variables.

Cells 2021 11 14;10(11). Epub 2021 Nov 14.

Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

Immunotherapy targeting the PD-1-PD-L1 axis yielded good results in treating different immunologically ''hot'' tumors. A phase II study revealed good therapeutic activity of pembrolizumab in selected prostatic carcinoma (PC)-patients. We performed a systematic literature review (PRISMA guidelines), which analyzes the immunohistochemical expression of PD-L1 in human PC samples and highlights the pre-analytical and interpretation variables. Interestingly, 29% acinar PCs, 7% ductal PCs, and 46% neuroendocrine carcinomas/tumors were PD-L1+ on immunohistochemistry. Different scoring methods or cut-off criteria were applied on variable specimen-types, evaluating tumors showing different clinic-pathologic features. The positivity rate of different PD-L1 antibody clones in tumor cells ranged from 3% (SP142) to 50% (ABM4E54), excluding the single case tested for RM-320. The most tested clone was E1L3N, followed by 22C3 (most used for pembrolizumab eligibility), SP263, SP142, and 28-8, which gave the positivity rates of 35%, 11-41% (depending on different scoring systems), 6%, 3%, and 15%, respectively. Other clones were tested in <200 cases. The PD-L1 positivity rate was usually higher in tumors than benign tissues. It was higher in non-tissue microarray specimens (41-50% vs. 15%), as PC cells frequently showed heterogenous or focal PD-L1-staining. PD-L1 was expressed by immune or stromal cells in 12% and 69% cases, respectively. Tumor heterogeneity, inter-institutional preanalytics, and inter-observer interpretation variability may account for result biases.
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http://dx.doi.org/10.3390/cells10113166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625301PMC
November 2021

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 2: Clinic-Pathologic Correlations.

Cells 2021 11 14;10(11). Epub 2021 Nov 14.

Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic-pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.
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http://dx.doi.org/10.3390/cells10113165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618408PMC
November 2021

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment.

Int J Mol Sci 2021 Nov 15;22(22). Epub 2021 Nov 15.

Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients' serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.
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http://dx.doi.org/10.3390/ijms222212330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618001PMC
November 2021

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1.

Int J Mol Sci 2021 Nov 15;22(22). Epub 2021 Nov 15.

Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.
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http://dx.doi.org/10.3390/ijms222212314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619683PMC
November 2021

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 4: Experimental Treatments in Pre-Clinical Studies (Cell Lines and Mouse Models).

Int J Mol Sci 2021 Nov 14;22(22). Epub 2021 Nov 14.

Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).
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http://dx.doi.org/10.3390/ijms222212297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618402PMC
November 2021

Management of colovesical fistula: a systematic review.

Minerva Urol Nephrol 2022 Aug 18;74(4):400-408. Epub 2021 Nov 18.

Unit of Surgical Oncology, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy.

Introduction: Colovesical fistulas (CVFs) account for approximately 95% enterovesical fistulas (EVFs). About 2/3 CVF cases are diverticular in origin. It mainly presents with urological signs such as pneumaturia and fecaluria. Diagnostic investigations aim at confirming the presence of a fistula. Although conservative management can be chosen for selected individuals, most patients are mainly treated through surgical interventions. CVF represents a challenging condition, which records high rates of morbidity and mortality. Our systematic review aimed at achieving deeper knowledge of both indications, in addition to short- and long-term outcomes related to CVF management.

Evidence Acquisition: We performed a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. Pubmed/MEDLINE, Embase, Scopus, Cochrane Library and Web of Science databases were used to search all related literature.

Evidence Synthesis: The 22 included articles covered an approximately 37 years-study period (1982-2019), with a total 1365 patient population. CVF etiology was colonic diverticulitis in most cases (87.9%). Pneumaturia (50.1%), fecaluria (40.9%) and urinary tract infections (46.6%) were the most common symptoms. Abdomen computed tomography (CT) scan (80.5%), colonoscopy (74.5%) and cystoscopy (55.9%) were the most frequently performed diagnostic methods. Most CVF patients underwent surgery (97.1%) with open approach (63.3%). Almost all patients had colorectal resection with primary anastomosis with or without ostomy and 53.2% patients underwent primary repair or partial/total cystectomy. Four percent anastomotic leak, 1.8% bladder leak and 3.1% reoperations rates were identified. In an average 5-68-month follow-up, overall morbidity, overall mortality and recurrences rates recorded were 8-49%, 0-63% and 1.2%, respectively.

Conclusions: CVF mainly affects males and has diverticular origin in almost all cases. Pneumaturia, fecaluria and urinary tract infections are the most characteristic symptoms. Endoscopic tests and imaging are critical tools for diagnostic completion. Management of CVFs depends on the underlying disease. Surgical treatment represents the final approach and consists of resection and reanastomosis of offending intestinal segment, with or without bladder closure. In many cases, a single-stage surgical strategy is selected. Perioperative and long-term outcomes prove good.
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http://dx.doi.org/10.23736/S2724-6051.21.04750-9DOI Listing
August 2022

Cutaneous Localization of Classic Hodgkin Lymphoma Associated with Mycosis Fungoides: Report of a Rare Event and Review of the Literature.

Life (Basel) 2021 Oct 11;11(10). Epub 2021 Oct 11.

Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy.

Mycosis fungoides and nodal classic Hodgkin lymphoma (cHL) have been reported to occur concurrently or sequentially in the same patient. A long-lasting mycosis fungoides more often precedes the onset of nodal cHL, although few cases of nodal cHL followed by mycosis fungoides have been observed. Skin involvement is a rare manifestation of cHL that may be observed in the setting of advanced disease. The decrease in skin involvement in cHL is mainly due to the improved therapeutic strategies. The concurrent presence of mycosis fungoides and cutaneous localization of classic Hodgkin lymphoma represents a very uncommon event, with only two cases reported so far. Herein, we describe the case of a 71-year-old man, with a history of recurrent nodal cHL, who developed MF and, subsequently, the cutaneous localization of cHL. The clinicopathological features of the two diseases are described focusing on the main differential diagnoses to be taken into consideration, and a review of the literature is performed.
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http://dx.doi.org/10.3390/life11101069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537882PMC
October 2021

EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 1).

Cancers (Basel) 2021 Sep 12;13(18). Epub 2021 Sep 12.

Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy.

EBV is the most common persistent virus in humans. The interaction of EBV with B lymphocytes, which are considered the virus reservoir, is at the base of the life-long latent infection. Under circumstances of immunosuppression, the balance between virus and host immune system is altered and hence, EBV-associated lymphoid proliferations may originate. These disorders encompass several entities, ranging from self-limited diseases with indolent behavior to aggressive lymphomas. The virus may infect not only B-cells, but even T- and NK-cells. The occurrence of different types of lymphoid disorders depends on both the type of infected cells and the state of host immunity. EBV-driven lymphoproliferative lesions can rarely occur in the gastrointestinal tract and may be missed even by expert pathologists due to both the uncommon site of presentation and the frequent overlapping morphology and immunophenotypic features shared by different entities. The aim of this review is to provide a comprehensive overview of the current knowledge of EBV-associated lymphoproliferative disorders, arising within the gastrointestinal tract. The review is divided in three parts. In this part, the available data on EBV biology, EBV-positive mucocutaneous ulcer, EBV-positive diffuse large B-cell lymphoma, not otherwise specified and classic Hodgkin lymphoma are discussed.
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http://dx.doi.org/10.3390/cancers13184578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465149PMC
September 2021

EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 2).

Cancers (Basel) 2021 Sep 8;13(18). Epub 2021 Sep 8.

Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy.

Epstein-Barr virus (EBV) is a common pathogen infecting people primarily early in life. The virus has the ability to persist throughout a person's life, usually in B lymphocytes. Conditions of immunodeficiency as well as the introduction of immunosuppressive therapies and the advent of transplant technologies has brought immunodeficiency-associated lymphoproliferative disorders into view, which are often driven by EBV. The group of EBV-associated lymphoproliferative disorders includes different entities, with distinct biological features, ranging from indolent disorders, which may even spontaneously regress, to aggressive lymphomas requiring prompt and adequate treatment. These disorders are often diagnostically challenging due to their overlapping morphology and immunophenotype. Both nodal and extra-nodal sites, including the gastrointestinal tract, may be involved. This review, divided in three parts, summarizes the clinical, pathological, molecular features and treatment strategies of EBV-related lymphoproliferative disorders occurring in the gastrointestinal tract and critically analyzes the major issues in the differential diagnosis. In this part of the review, we discuss plasmablastic lymphoma, extra-cavitary primary effusion lymphoma and Burkitt lymphoma.
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http://dx.doi.org/10.3390/cancers13184527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469260PMC
September 2021

Case Report: Contrasting BCL2 Upregulation With Venetoclax in a Case of Refractory Lymphomatoid Papulosis and Progressive Chronic Lymphocytic Leukemia.

Front Oncol 2021 9;11:729106. Epub 2021 Sep 9.

Institute of Hematology-Centro di Ricerca Emato-Oncologica (CREO), Department of Medicine and Surgery, University of Perugia, Perugia, Italy.

A 57-year-old man affected by high-risk progressive chronic lymphocytic leukemia (CLL), primary resistant to first-line chemoimmunotherapy, developed a type A lymphomatoid papulosis (LyP) during a second progression of CLL. The two blood tumor entities were clonally unrelated. LyP presented with a diffuse (>90% body surface area) cutaneous rash and was characterized by intensely pruriginous dusky nodules (n = 10) and red flat-topped papules (n = 60). No response to topical corticosteroids and psoralen plus ultraviolet A (PUVA) phototherapy was observed. In order to effectively treat progressive -mutated CLL, the potent BCL2 inhibitor, venetoclax, was initiated with no treatment-related complications. While CLL only achieved a partial response, a complete remission of LyP-associated cutaneous rash and of the intractable pruritus was obtained within 2 months from venetoclax initiation. BCL2 immunostaining of the original cutaneous specimen showed a strong over-expression of the anti-apoptotic protein, restricted to CD30 lymphoid cells and reactive microenvironment. At 12 months follow-up, the patient is still in complete remission of LyP. Our findings underline the probable pathogenic role of BCL2 in LyP and the potential therapeutic efficacy of venetoclax for the treatment of this primary cutaneous CD30 lymphoproliferative disorder, especially in the setting of severe and refractory disease.
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http://dx.doi.org/10.3389/fonc.2021.729106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459905PMC
September 2021

Novel NPM1 exon 5 mutations and gene fusions leading to aberrant cytoplasmic nucleophosmin in AML.

Blood 2021 12;138(25):2696-2701

Munich Leukemia Laboratory, Munich, Germany.

Nucleophosmin (NPM1) mutations in acute myeloid leukemia (AML) affect exon 12, but also sporadically affect exons 9 and 11, causing changes at the protein C-terminal end (tryptophan loss, nuclear export signal [NES] motif creation) that lead to aberrant cytoplasmic NPM1 (NPM1c+), detectable by immunohistochemistry. Combining immunohistochemistry and molecular analyses in 929 patients with AML, we found non-exon 12 NPM1 mutations in 5 (1.3%) of 387 NPM1c+ cases. Besides mutations in exons 9 (n = 1) and 11 (n = 1), novel exon 5 mutations were discovered (n = 3). Another exon 5 mutation was identified in an additional 141 patients with AML selected for wild-type NPM1 exon 12. Three NPM1 rearrangements (NPM1/RPP30, NPM1/SETBP1, NPM1/CCDC28A) were detected and characterized among 13 979 AML samples screened by cytogenetic/fluorescence in situ hybridization and RNA sequencing. Functional studies demonstrated that in AML cases, new NPM1 proteins harbored an efficient extra NES, either newly created or already present in the fusion partner, ensuring its cytoplasmic accumulation. Our findings support NPM1 cytoplasmic relocation as critical for leukemogenesis and reinforce the role of immunohistochemistry in predicting AML-associated NPM1 genetic lesions. This study highlights the need to develop new assays for molecular diagnosis and monitoring of NPM1-mutated AML.
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http://dx.doi.org/10.1182/blood.2021012732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037756PMC
December 2021

Gastrointestinal Manifestations in Systemic Mastocytosis: The Need of a Multidisciplinary Approach.

Cancers (Basel) 2021 Jul 1;13(13). Epub 2021 Jul 1.

Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy.

Mastocytosis represents a heterogeneous group of neoplastic mast cell disorders. The basic classification into a skin-limited disease and a systemic form with multi-organ involvement remains valid. Systemic mastocytosis is a disease often hard to diagnose, characterized by different symptoms originating from either the release of mast cell mediators or organ damage due to mast cell infiltration. Gastrointestinal symptoms represent one of the major causes of morbidity, being present in 60-80% of patients. A high index of suspicion by clinicians and pathologists is required to reach the diagnosis. Gastrointestinal mastocytosis can be a challenging diagnosis, as symptoms simulate other more common gastrointestinal diseases. The endoscopic appearance is generally unremarkable or nonspecific and gastrointestinal mast cell infiltration can be focal and subtle, requiring an adequate sampling with multiple biopsies by the endoscopists. Special stains, such as CD117, tryptase, and CD25, should be performed in order not to miss the gastrointestinal mast cell infiltrate. A proper patient's workup requires a multidisciplinary approach including gastroenterologists, endoscopists, hematologists, oncologists, and pathologists. The aim of this review is to analyze the clinicopathological features of gastrointestinal involvement in systemic mastocytosis, focusing on the relevance of a multidisciplinary approach.
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http://dx.doi.org/10.3390/cancers13133316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269078PMC
July 2021
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