Silvia Uccella
@hunimed.eu
Humanitas University
RESEARCH, TEACHING, or OTHER INTERESTS
Pathology and Forensic Medicine, Oncology, Endocrinology, Diabetes and Metabolism, Hematology
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Giuseppe Pelosi, Valentina Melocchi, Elisa Dama, Paul Hofman, Marco De Luca, Adriana Albini, Maria Gemelli, Riccardo Ricotta, Mauro Papotti, Stefano La Rosa,et al.
Elsevier BV
Silvia Uccella
Springer Science and Business Media LLC
AbstractIn the last two decades, the increasing availability of technologies for molecular analyses has allowed an insight in the genomic alterations of neuroendocrine neoplasms (NEN) of the gastrointestinal tract and pancreas. This knowledge has confirmed, supported, and informed the pathological classification of NEN, clarifying the differences between neuroendocrine carcinomas (NEC) and neuroendocrine tumors (NET) and helping to define the G3 NET category. At the same time, the identification genomic alterations, in terms of gene mutation, structural abnormalities, and epigenetic changes differentially involved in the pathogenesis of NEC and NET has identified potential molecular targets for precision therapy. This review critically recapitulates the available molecular features of digestive NEC and NET, highlighting their correlates with pathological aspects and clinical characteristics of these neoplasms and revising their role as predictive biomarkers for targeted therapy. In this context, the feasibility and applicability of a molecular classification of gastrointestinal and pancreatic NEN will be explored.
Francesca Spada, Massimo Milione, Patrick Maisonneuve, Natalie Prinzi, Valeria Smiroldo, Elena Bolzacchini, Sara Pusceddu, Carlo Carnaghi, Fausto Sessa, Stefano La Rosa,et al.
Springer Science and Business Media LLC
Roberta Sciarra, Michele Merli, Caterina Cristinelli, Marco Lucioni, Silvia Zibellini, Roberta Riboni, Daniela Furlan, Silvia Uccella, Caterina Zerbi, Benedetta Bianchi,et al.
Wiley
SummaryHepatitis C virus (HCV)‐associated diffuse large B‐cell lymphoma (DLBCL) displays peculiar clinicopathological characteristics, but its molecular landscape is not fully elucidated. In this study, we investigated the clinicopathological and molecular features of 54 patients with HCV‐associated DLBCL. The median age was 71 years. An underlying marginal zone lymphoma component was detected in 14.8% of cases. FISH analysis showed rearrangements involving BCL6 in 50.9% of cases, MYC in 11.3% and BCL2 in 3.7%. Lymph2Cx‐based assay was successful in 38 cases, recognizing 16 cases (42.1%) as ABC and 16 cases as GCB subtypes, while six resulted unclassified. ABC cases exhibited a higher lymphoma‐related mortality (LRM). Next‐generation sequencing analysis showed mutations in 158/184 evaluated genes. The most frequently mutated genes were KMT2D (42.6%), SETD1B (33.3%), RERE (29.4%), FAS and PIM1 (27.8%) and TBL1XR1 (25.9%). A mutation in the NOTCH pathway was detected in 25.9% of cases and was associated with worst LRM. Cluster analysis by LymphGen classified 29/54 cases within definite groups, including BN2 in 14 (48.2%), ST2 in seven (24.2%) and MCD and EZB in four each (13.8%). Overall, these results indicate a preferential marginal zone origin for a consistent subgroup of HCV‐associated DLBCL cases and suggest potential implications for molecularly targeted therapies.
Erica Reggi, Simon Kaiser, Nora Sahnane, Silvia Uccella, Stefano La Rosa, and Dario Diviani
Elsevier BV
Elena Russo, Mathilda Guizzardi, Luca Canali, Francesca Gaino, Andrea Costantino, Gherardo Mazziotti, Andrea Lania, Silvia Uccella, Luca Di Tommaso, Fabio Ferreli,et al.
Springer Science and Business Media LLC
Silvia Uccella, Matthias Dottermusch, Lori Erickson, Julia Warmbier, Kathleen Montone, and Wolfgang Saeger
Springer Science and Business Media LLC
Sylvia L. Asa, Silvia Uccella, and Arthur Tischler
Springer Science and Business Media LLC
Silvia Uccella, Eleonora Leoni, Simon Kaiser, Roberta Maragliano, Alessandro Valerio, Laura Libera, Maria Laura Tanda, Marco Volante, Dario Diviani, and Stefano La Rosa
Springer Science and Business Media LLC
Andrea Coppola, Tonia Gatta, Giacomo Maria Pini, Giorgia Scordi, Federico Fontana, Filippo Piacentino, Roberto Minici, Domenico Laganà, Antonio Basile, Federico Dehò,et al.
MDPI AG
Background: We present a case series of Neuroendocrine Carcinoma of the Urinary Bladder (NECB) to analyse their radiologic appearance on CT, find a “Radiomic signature”, and review the current literature. Methods: 14 CT cases of NECB were reviewed and compared with a control group of 42 patients with high-grade non-neuroendocrine bladder neoplasm for the following parameters: ring enhancement; implantation site; dimensions; density; margins; central necrosis; calcifications; number of lesions; wall thickness; depth of invasion in the soft tissue; invasion of fat tissue; invasion of adjacent organs; lymph-node involvement; abdominal organ metastasis. To extract radiomic features, volumes of interest of bladder lesions were manually delineated on the portal-venous phase. The radiomic features of the two groups were identified and compared. Results: Statistical differences among NECB and control group were found in the prevalence of male sex (100% vs. 69.0%), hydronephrosis (71.4% vs. 33.3%), mean density of the mass (51.01 ± 15.48 vs. 76.27 ± 22.26 HU); product of the maximum diameters on the axial plane (38.1 ± 59.3 vs. 14.44 ± 12.98 cm2) in the control group, trigonal region involvement (78.57% vs. 19.05%). About the radiomic features, Student’s t-test showed significant correlation for the variables: “DependenceNonUniformity” (p: 0.048), “JointAverage” (p: 0.013), “LargeAreaLowGrayLevelEmphasis” (p: 0.014), “Maximum2DDiameterColumn” (p: 0.04), “Maximum 2DDiameterSlice” (p: 0.007), “MeanAbsoluteDeviation” (p: 0.021), “BoundingBoxA” (p: 0.022) and “CenterOfMassB” (p: 0.007). Conclusions: There is a typical pattern (male patient, large mass, trigonal area involvement) of NECB presentation on contrast-enhanced CT. Certain morphological characteristics and encouraging results about Radiomic features can help define the diagnosis.
Amedeo Sciarra, Silvia Uccella, Philippe Hiroz, Ian Fournier, Vincent Soubeyran, Giovanna Finzi, and Stefano La Rosa
Springer Science and Business Media LLC
Roberta Elisa Rossi, Elisabetta Lavezzi, Simona Jaafar, Giacomo Cristofolini, Alice Laffi, Gennaro Nappo, Silvia Carrara, Alexia Francesca Bertuzzi, Silvia Uccella, Alessandro Repici,et al.
MDPI AG
Carcinoid syndrome (CS), mostly associated with small intestinal neuroendocrine tumors (SI-NETs) or lung-related NETs, is characterized by symptoms related to hormonal secretion and long-term complications, including carcinoid heart disease (CHD), which is potentially life-threatening. In the early stages of the disease, symptoms are non-specific, which leads to delayed diagnoses. The availability of reliable tumor markers is crucial for a prompt diagnosis and proper management. This review summarizes available evidence on the role of 24 h urinary 5-hydroxyindolacetic acid (24u5HIAA), which is the urinary breakdown metabolite of serotonin, in the diagnosis/follow-up of NET-related CS, with a focus on its potential prognostic role, while eventually attempting to suggest a timeline for its measurement during the follow-up of NET patients. The use of 24u5HIAA is an established biomarker for the diagnosis of NETs with CS since it shows a sensibility and specificity of 100% and 85–90%, respectively. The downside of 24u5-HIAA is represented by the need for 24 h urine collection and the risk of confounding factors (foods and medication), which might lead to false positive/negative results. Moreover, 24u5HIAA is useful in the follow-up of NETs with CS since a shorter double time correlates to a higher risk of disease progression/disease-specific mortality. Furthermore, an elevation in 24u5-HIAA is correlated with a dismal prognosis because it is associated with an increased likelihood of CHD development and disease progression/mortality. Other potentially interesting biochemical markers have been proposed, including plasmatic 5HIAA, although further standardization and prospective studies are required to define their role in the management of NETs. Meanwhile, 24u5HIAA remains the most accurate CS biomarker.
E. Dainese, L. Cimetti, B. Pozzi, M. Milani, G. Russo, S. Castelnuovo, C.V. Viganò, M. Cerati, S. Uccella, and A. Vanzati
Elsevier BV
Silvia Uccella, Gaia Goteri, Antonino Maiorana, Valentina Donati, Maria Grazia Tibiletti, Francesca Magnoli, Sofia Facchi, Deborah Merchiori, Erika Morsia, Robel Papotti,et al.
Elsevier BV
Francesca Magnoli, Deborah Marchiori, Sofia Facchi, Vittoria Martin, Leonardo Campiotti, Michele Merli, Fausto Sessa, Maria Grazia Tibiletti, and Silvia Uccella
Elsevier BV
Sara Fraticelli, Marco Lucioni, Giuseppe Neri, Deborah Marchiori, Caterina Cristinelli, Michele Merli, Rodolfo Monaco, Tiziana Borra, Antonio Lazzaro, Silvia Uccella,et al.
MDPI AG
Castleman disease (CD) is a rare lymphoproliferative disorder that includes various clinico-pathological subtypes. According to clinical course, CD is divided into unicentric CD (UCD) and multicentric CD (MCD). MCD is further distinguished based on the etiological driver in herpes virus-8-related MCD (that can occur in the setting of HIV); in MCD associated with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes); and idiopathic MCD (iMCD). The latter can also be divided in iMCD-TAFRO (thrombocytopenia, anasarca, fever, myelofibrosis, organomegaly) and iMCD not otherwise specified. To date, CD pathogenesis is still uncertain, but CD may represent the histological and clinical result of heterogeneous pathomechanisms. Transcriptome investigations in CD lymph nodes have documented the expression and up-regulation of different cytokines; furthermore, few recent studies have shown alterations of different T-cell subsets in CD patients, suggesting a possible role of the nodal microenvironment in CD development. On this basis, our study aimed to investigate the distribution of T-cell subsets in the clinico-pathological spectrum of CD. We evaluated the CD4/CD8 ratio and the number of T-regulatory (T-reg) FOXP3+ cells in 28 CD cases. In total, 32% of cases showed a decreased CD4/CD8 ratio due to increased CD8+ T-cells, including both UCD, iMCD, and HHV8+ MCD cases. The T-reg subset analysis revealed a statistically significant (p < 0.0001) lower mean number of FOXP3+ T-reg cells in CD cases when compared with non-specific reactive lymph nodes. We did not find statistically significant differences in T-reg numbers between the different CD subtypes. These findings may suggest that alterations in T-cell subpopulations that can lead to disruption of immune system control may contribute to the numerous changes in different cellular compartments that characterize CD.
Abbas Agaimy, Atsuko Kasajima, Robert Stoehr, Florian Haller, Christoph Schubart, Lars Tögel, Nicole Pfarr, Alexander von Werder, Marianne E. Pavel, Fausto Sessa,et al.
Springer Science and Business Media LLC
Abstract Ectopic Cushing syndrome is a rare clinical disorder resulting from excessive adrenocorticotrophic hormone (ACTH) produced by non-pituitary neoplasms, mainly neuroendocrine neoplasms (NENs) of the lung, pancreas, and gastrointestinal tract, and other less common sites. The genetic background of ACTH-producing NENs has not been well studied. Inspired by an index case of ACTH-producing pancreatic NEN carrying a gene fusion, we postulated that ACTH-producing NENs might be enriched for gene fusions. We herein examined 21 ACTH-secreting NENs of the pancreas (10), lung (9), thymus (1), and kidney (1) using targeted RNA sequencing. The tumors were classified according to the most recent WHO classification as NET-G1/typical carcinoid (n = 4), NETG-2/atypical carcinoid (n = 14), and NET-G3 (n = 3). Overall, targeted RNA sequencing was successful in 11 cases (4 of 10 pancreatic tumors, 5 of 9 pulmonary tumors, and in the one renal and one thymic tumor). All four successfully tested pancreatic tumors revealed a gene fusion: two had a EWSR1::BEND2 and one case each had a KMT2A::BCOR and a TFG::ADGRG7 fusion, respectively. EWSR1 rearrangements were confirmed in both tumors with a EWSR1::BEND2 by FISH. Gene fusions were mutually exclusive with ATRX, DAXX, and MEN1 mutations (the most frequently mutated genes in NETs) in all four cases. Using RNA-based variant assessment (n = 16) or via the TSO500 panel (n = 5), no pathogenic BCOR mutations were detected in any of the cases. Taken together, gene fusions were detected in 4/4 (100%) pancreatic versus 0/7 (0%) non-pancreatic tumors, respectively. These results suggest a potential role for gene fusions in triggering the ACTH production in pancreatic NENs presenting with ectopic Cushing syndrome. While the exact mechanisms responsible for the ectopic ACTH secretion are beyond the scope of this study, overexpressed fusion proteins might be involved in promoter-mediated overexpression of pre-ACTH precursors in analogy to the mechanisms postulated for EWSR1::CREB1-mediated paraneoplastic phenomena in certain mesenchymal neoplasms. The genetic background of the ACTH-producing non-pancreatic NENs remains to be further studied.
Elena Russo, Mathilda Guizzardi, Luca Canali, Francesca Gaino, Andrea Costantino, Gherardo Mazziotti, Andrea Lania, Silvia Uccella, Luca Di Tommaso, Fabio Ferreli,et al.
Springer Science and Business Media LLC
E. Vitali, G. Valente, A. Panzardi, A. Laffi, A. Zerbi, S. Uccella, G. Mazziotti, and A. Lania
Springer Science and Business Media LLC
Saverio Pancetti, Daoud Rahal, Bethania Fernades, Carlo Galli, Silvia Uccella, Luigi Maria Terracciano, Federico Pessina, Lorenzo Bello, and Arturo Bonometti
MDPI AG
Primary large B-cell lymphoma of immune-privileged sites (IP-LBCL) is a rare malignant hematological neoplasm. Involvement of the cerebellum is even rarer and its diagnosis is often difficult to make due to its non-specific clinical and radiological presentation. Methods: We reported 3 cases of cerebellar IP-LBCL followed at our hospital and reviewed the medical literature to unravel the peculiarities of this poorly studied entity. Outcomes: Analyzing our cases and reviewing the literature, we could collect and study 26 cases of cerebellar IP-LBCL. To the best of our knowledge, this is the largest cohort of such patients currently published. Conclusion: Cerebellar IP-LBCL presents more often in adult females with cerebellum-related focal neurological signs such as ataxia, headache, and nausea. Histological confirmation is mandatory for a correct diagnosis and treatment and all cases feature diffuse large B-cell lymphoma histopathology. Compared to other encephalic IP-LBCL, cerebellar cases seem to include a higher number of cases with germinal center B-cell phenotype and better survival. These differences may be related to a different immune microenvironment and especially immunoregulation that distinguishes the cerebellum from other areas of the CNS.
Annick Mühlethaler-Mottet, Silvia Uccella, Deborah Marchiori, Stefano La Rosa, Jean Daraspe, Katia Balmas Bourloud, Maja Beck Popovic, Philippe J. Eugster, Eric Grouzmann, and Karim Abid
Frontiers Media SA
IntroductionNeuroblastoma (NB) is a pediatric cancer of the developing sympathetic nervous system. It produces and releases metanephrines, which are used as biomarkers for diagnosis in plasma and urine. However, plasma catecholamine concentrations remain generally normal in children with NB. Thus, unlike pheochromocytoma and paraganglioma (PHEO/PGL), two other non-epithelial neuroendocrine tumors, hypertension is not part of the usual clinical picture of patients with NB. This suggests that the mode of production and secretion of catecholamines and metanephrines in NB is different from that in PHEO/PGL, but little is known about these discrepancies. Here we aim to provide a detailed comparison of the biosynthesis, metabolism and storage of catecholamines and metanephrines between patients with NB and PHEO.MethodCatecholamines and metanephrines were quantified in NB and PHEO/PGL patients from plasma and tumor tissues by ultra-high pressure liquid chromatography tandem mass spectrometry. Electron microscopy was used to quantify neurosecretory vesicles within cells derived from PHEO tumor biopsies, NB-PDX and NB cell lines. Chromaffin markers were detected by qPCR, IHC and/or immunoblotting.ResultsPlasma levels of metanephrines were comparable between NB and PHEO patients, while catecholamines were 3.5-fold lower in NB vs PHEO affected individuals. However, we observed that intratumoral concentrations of metanephrines and catecholamines measured in NB were several orders of magnitude lower than in PHEO. Cellular and molecular analyses revealed that NB cell lines, primary cells dissociated from human tumor biopsies as well as cells from patient-derived xenograft tumors (NB-PDX) stored a very low amount of intracellular catecholamines, and contained only rare neurosecretory vesicles relative to PHEO cells. In addition, primary NB expressed reduced levels of numerous chromaffin markers, as compared to PHEO/PGL, except catechol O-methyltransferase and monoamine oxidase A. Furthermore, functional assays through induction of chromaffin differentiation of the IMR32 NB cell line with Bt2cAMP led to an increase of neurosecretory vesicles able to secrete catecholamines after KCl or nicotine stimulation.ConclusionThe low amount of neurosecretory vesicles in NB cytoplasm prevents catecholamine storage and lead to their rapid transformation by catechol O-methyltransferase into metanephrines that diffuse in blood. Hence, in contrast to PHEO/PGL, catecholamines are not secreted massively in the blood, which explains why systemic hypertension is not observed in most patients with NB.
Jasna Metovic, Eliano Cascardi, Silvia Uccella, Roberta Maragliano, Giulia Querzoli, Simona Osella-Abate, Alessandra Pittaro, Stefano La Rosa, Giuseppe Bogina, Paola Cassoni,et al.
Springer Science and Business Media LLC
Abstract The classification of breast neuroendocrine neoplasms (Br-NENs) was modified many times over the years and is still a matter of discussion. In the present study, we aimed to evaluate the diagnostic reproducibility and impact on patient outcomes of the most recent WHO 2019 edition of breast tumor classification, namely, for neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). This multicentric observational study included 287 breast neoplasms with NE differentiation. The cases were blindly classified by three independent groups of dedicated breast and/or endocrine pathologists following the 2019 guidelines. Diagnostic concordance and clinical impact were assessed. We observed only a moderate overall diagnostic agreement across the three centers (Cohen’s kappa 0.4532) in distinguishing NET from solid papillary carcinomas (SPCs) and no special type carcinomas (NST) with NE differentiation. Br-NENs were diagnosed in 122/287 (42.5%) cases, subclassified as 11 NET G1 (3.8%), 84 NET G2 (29.3%), and 27 NEC (9.4%), the latter group consisting of 26 large-cell and 1 small-cell NECs. The remaining 165/287 (57.5%) cases were labeled as non-NEN, including SPC, mucinous, NST, and mixed NE carcinomas. While NET and non-NEN cases had a comparable outcome, the diagnosis of NECs showed negative impact on disease-free interval compared to NETs and non-NENs (p = 0.0109). In conclusion, the current diagnostic classification of Br-NENs needs further adjustments regarding morphological and immunohistochemical criteria to increase the diagnostic reproducibility among pathologists. Our data suggest that, apart from high-grade small- and large-cell NECs, Br-NENs behave like non-NEN breast carcinomas and should be managed similarly.
Roberto Fiore, Stefano La Rosa, Silvia Uccella, Deborah Marchiori, and Peter A Kopp
Bioscientifica
Introduction Consumptive hypothyroidism is a rare paraneoplastic condition most commonly associated with infantile hemangiomas. It is caused by overexpression of deiodinase type 3 (D3), which leads to preferential conversion of thyroxine to the metabolically inactive reverse triiodothyronine (rT3), paralleled by a decrease of the biologically active T3. Case presentation A 46-year-old male patient with previously normal thyroid function was diagnosed with a renal carcinoma with rhabdoid differentiation. He was treated with sunitinib, followed by the immune checkpoint inhibitors ipilimumab and nivolumab, and he developed primary hypothyroidism secondary to thyroiditis. Substitution with unusually high doses of levothyroxine as high as 4.3 µg/kg/day did not normalize his thyroid function. Poor compliance was refuted because there was no improvement after observed administration. He had no malabsorption. Although tyrosine kinase inhibitors can increase the expression of D3, this effect tends to be modest. Therefore, the suspicion of tumor-related consumptive hypothyroidism was raised and supported by low free T3 and elevated rT3 levels. The therapy could not be further modified because the patient opted for palliative care and passed away 12 days later. Immunohistochemistry of the tumor from a sample obtained prior to systemic therapy documented abundant expression of D3, corroborating the diagnosis of consumptive hypothyroidism. Conclusions This observation extends the spectrum of malignancies overexpressing D3. Although rare, increased awareness of this paraneoplastic syndrome is key, if persistent hypothyroidism cannot be explained by compliance issues or malabsorption. Substitution with high doses of levothyroxine, and combination therapy with liothyronine, can correct hypothyroidism in these patients.
Francesca Magnoli, Lorenzo Casiccia, Francesco Ripamonti, and Silvia Uccella
Springer Science and Business Media LLC
Roberta Maragliano, Laura Libera, Ileana Carnevali, Valeria Pensotti, Giovanna De Vecchi, Margherita Testa, Cristina Amaglio, Eleonora Leoni, Giorgio Formenti, Fausto Sessa,et al.
Springer Science and Business Media LLC
AbstractPrimary ovarian neuroendocrine neoplasms (Ov-NENs) are infrequent and mainly represented by well-differentiated forms (neuroendocrine tumors — NETs — or carcinoids). Poorly differentiated neuroendocrine carcinomas (Ov-NECs) are exceedingly rare and only few cases have been reported in the literature. A subset of Ov-NECs are admixed with non-neuroendocrine carcinomas, as it occurs in other female genital organs, as well (mostly endometrium and uterine cervix), and may be assimilated to mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs) described in digestive and extra-digestive sites. Here, we present a case of large cell Ov-NEC admixed with an endometrioid carcinoma of the ovary, arising in the context of ovarian endometriosis, associated with a uterine endometrial atypical hyperplasia (EAH). We performed targeted next-generation sequencing analysis, along with a comprehensive immunohistochemical study and FISH analysis for TP53 locus, separately on the four morphologically distinct lesions (Ov-NEC, endometrioid carcinoma, endometriosis, and EAH). The results of our study identified molecular alterations of cancer-related genes (PIK3CA, CTNNB1, TP53, RB1, ARID1A, and p16), which were present with an increasing gradient from preneoplastic lesions to malignant proliferations, both neuroendocrine and non-neuroendocrine components. In conclusion, our findings underscored that the two neoplastic components of this Ov-MiNEN share a substantially identical molecular profile and they progress from a preexisting ovarian endometriotic lesion, in a patient with a coexisting preneoplastic proliferation of the endometrium, genotypically and phenotypically related to the ovarian neoplasm. Moreover, this study supports the inclusion of MiNEN in the spectrum ovarian and, possibly, of all gynecological NENs, among which they are currently not classified.