Publications by authors named "Mauro Papotti"

355 Publications

Automated Analysis of Proliferating Cells Spatial Organisation Predicts Prognosis in Lung Neuroendocrine Neoplasms.

Cancers (Basel) 2021 Sep 29;13(19). Epub 2021 Sep 29.

Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.

Lung neuroendocrine neoplasms (lung NENs) are categorised by morphology, defining a classification sometimes unable to reflect ultimate clinical outcome. Subjectivity and poor reproducibility characterise diagnosis and prognosis assessment of all NENs. Here, we propose a machine learning framework for tumour prognosis assessment based on a quantitative, automated and repeatable evaluation of the spatial distribution of cells immunohistochemically positive for the proliferation marker Ki-67, performed on the entire extent of high-resolution whole slide images. Combining features from the fields of graph theory, fractality analysis, stochastic geometry and information theory, we describe the topology of replicating cells and predict prognosis in a histology-independent way. We demonstrate how our approach outperforms the well-recognised prognostic role of Ki-67 Labelling Index on a multi-centre dataset comprising the most controversial lung NENs. Moreover, we show that our system identifies arrangement patterns in the cells positive for Ki-67 that appear independently of tumour subtyping. Strikingly, the subset of these features whose presence is also independent of the value of the Labelling Index and the density of Ki-67-positive cells prove to be especially relevant in discerning prognostic classes. These findings disclose a possible path for the future of grading and classification of NENs.
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http://dx.doi.org/10.3390/cancers13194875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508355PMC
September 2021

Real-World Data on NGS Diagnostics: a survey from the Italian Society of Pathology (SIAPeC) NGS Network.

Pathologica 2021 Aug;113(4):262-271

Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.

Next Generation Sequencing (NGS) is increasingly used in diagnostic centers for the assessment of genomic alterations to select patients for precision oncology. The Italian Society of Anatomic Pathology and Diagnostic Cytopathology (SIAPEC) through the Molecular Pathology and Predictive Medicine Study Group (PMMP) has been following the progressive development of centers that have adopted NGS technology in diagnostics over time. In July 2017, a study network on massive parallel sequencing was activated in Italy and recognized as the NGS SIAPeC National Network by the SIAPeC Scientific Society Board. Since then, activities have been implemented within the network that provide for alignment of laboratories through diagnostic concordance analysis and monitoring of centers adhering to the Network. Recently, considering the growing need for extended genomic analyses, the PMMP distributed a national survey to assess activities related to the use of genomic diagnostics in oncology within the NGS SIAPEC National Network.

Thirty centers participated in the survey. Eighty percent of the centers are laboratories within Pathology Departments. The distribution of laboratories in the country, the diagnostic laboratory/population ratio, the staff dedicated, the type and number of sequencing and mechatronics platforms available, the genomic panels utilized, and the type and number of diagnostic tests carried out in the last year in each center, are reported.

The centers were also asked whether they participated in a multidisciplinary Molecular Tumor Board (MTB) for management of patients. Thirty percent of the centers had a MTB that was ratified by regional decree. The professionals most frequently involved in the core team of the MTB are the pathologist, oncologist, molecular biologist, geneticist, pharmacologist, and bioinformatician.

The data from this survey indicate that NGS diagnostics in Italy is still heterogeneous in terms of geographical distribution and the characteristics of laboratories and diagnostic test performed. The implementation of activities that favors harmonization, the logistics and the convergence of biological material in reference centers for molecular analyses is a priority for the development of a functional laboratory network.
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http://dx.doi.org/10.32074/1591-951X-324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488986PMC
August 2021

Immunohistochemical typing of amyloid in fixed paraffin-embedded samples by an automatic procedure: Comparison with immunofluorescence data on fresh-frozen tissue.

PLoS One 2021 24;16(8):e0256306. Epub 2021 Aug 24.

Pathology Unit, City of Health and Science Hospital, Turin, Italy.

Amyloidosis comprises a spectrum of disorders characterized by the extracellular deposition of amorphous material, originating from an abnormal serum protein. The typing of amyloid into its many variants represents a pivotal step for a correct patient management. Several methods are currently used, including mass spectrometry, immunofluorescence, immunohistochemistry, and immunogold labeling. The aim of the present study was to investigate the accuracy and reliability of immunohistochemistry by means of a recently developed amyloid antibody panel applicable on fixed paraffin-embedded tissues in an automated platform. Patients with clinically and pathologically proven amyloidosis were divided into two cohorts: a pilot one, which included selected amyloidosis cases from 2009 to 2018, and a retrospective one (comprising all consecutive amyloidosis cases analyzed between November 2018 and May 2020). The above-referred panel of antibodies for amyloid classification was tested in all cases using an automated immunohistochemistry platform. When fresh-frozen material was available, immunofluorescence was also performed. Among 130 patients, a total of 143 samples from different organs was investigated. They corresponded to 51 patients from the pilot cohort and 79 ones from the retrospective cohort. In 82 cases (63%), fresh-frozen tissue was tested by immunofluorescence, serving to define amyloid subtype only in 30 of them (36.6%). On the contrary, the automated immunohistochemistry procedure using the above-referred new antibodies allowed to establish the amyloid type in all 130 cases (100%). These included: ALλ (n = 60, 46.2%), ATTR (n = 29, 22.3%), AA (n = 19, 14.6%), ALκ (n = 18, 13.8%), ALys (n = 2, 1.5%), and Aβ2M amyloidosis (n = 2, 1.5%). The present immunohistochemistry antibody panel represents a sensitive, reliable, fast, and low-cost method for amyloid typing. Since immunohistochemistry is available in most pathology laboratories, it may become the new gold standard for amyloidosis classification, either used alone or combined with mass spectrometry in selected cases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256306PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384180PMC
August 2021

Reply to: Spread Through Air Spaces (STAS): Can an Artifact Really be Excluded?

Am J Surg Pathol 2021 10;45(10):1439-1440

Pathology Unit, Department of Oncology, Città della Salute e della Scienza Hospital.

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http://dx.doi.org/10.1097/PAS.0000000000001791DOI Listing
October 2021

Pituitary metastases from neuroendocrine neoplasms: case report and narrative review.

Pituitary 2021 Oct 3;24(5):828-837. Epub 2021 Aug 3.

Oncological Endocrinology Unit, Department of Medical Sciences, University of Turin, Turin, Italy.

Purpose: Pituitary metastases (PM) are uncommon findings and are mainly derived from breast and lung cancers. No extensive review of PM from neuroendocrine neoplasms (NENs) is on record. Here we describe a clinical case of PM from pancreatic NEN and review the clinical features of PM from NENs reported in the literature.

Methods: A case of PM from a pancreatic NEN followed at our institution is described. We also reviewed the 43 cases of PM from NENs reported in the literature.

Results: A 59-year old female patient, previously submitted to duodeno-cephalo-pancreasectomy for a well-differentiated pancreatic NEN, with known hepatic metastases, underwent a  Ga-DOTATOC PET/CT that revealed an uptake in the pituitary gland. A subsequent MRI displayed a pituitary lesion, with suprasellar extension. After a hormonal and genetic diagnostic workup that excluded the diagnosis of MEN 1, the worsening of headache and visual impairment and the growth of the lesion lead to its surgical removal. A pituitary localization of the pancreatic NEN was identified. Regarding the published cases of PM from NENs, the most common tumour type was small cell lung cancer (SCLC), accounting for nearly half of the cases, followed by bronchial and pancreatic well differentiated NENs. The most frequent symptom was a variable degree of visual impairment, while headache was reported in half of the cases. Partial or total anterior hypopituitarism was present in approximately three quarters of the cases, while diabetes insipidus was less common. The most frequent treatment for PM was surgical resection, followed by radiotherapy and chemotherapy. The clinical outcome was in line with previous reports of PM from solid tumours, with a median survival of 14 months. Surgery of PM was associated with prolonged survival.

Conclusions: PM from NENs have clinical features similar to metastases derived from other solid tumours, albeit the involvement of the anterior pituitary seems more frequent; a thorough pituitary hormonal evaluation is mandatory, after focused radiological studies, particularly if a surgical approach is considered. The optimal management of PM remains disputed and seems mainly driven by the aggressiveness of the primary tumour and the presence of symptoms. In well-differentiated NENs, particularly in the case of symptomatic PM, surgical removal may be a reasonable approach.
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http://dx.doi.org/10.1007/s11102-021-01178-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416815PMC
October 2021

Caveolin-1 expression predicts favourable outcome and correlates with mutations in gastrointestinal stromal tumours (GISTs).

J Clin Pathol 2021 Jun 21. Epub 2021 Jun 21.

Pathology Unit, Department of Medical Sciences, University of Turin, Turin, Italy

Aims: Novel prognostic markers are warranted for gastrointestinal stromal tumours. Caveolin-1 is a multifunctional protein that proved to be associated with outcome in multiple tumour types. Aim of this study was to investigate Caveolin-1 expression and prognostic efficacy in a series of gastrointestinal stromal tumours.

Methods: Caveolin-1 expression was assessed by immunohistochemistry in a retrospective series of 66 gastrointestinal stromal tumours representative of the different molecular subtypes. Correlations with clinical, histopathological and molecular features were investigated. Statistical analyses were performed as appropriate.

Results: Thirty-five cases out of 66 (53.0%) expressed Caveolin-1. Presence of Caveolin-1 expression correlated with favourable histopathologic and clinical traits, including a lower mitotic count (p=0.003) and lower relapse rate (p=0.005). Caveolin-1 expression also resulted associated with the presence of mutations (p=0.010). Outcome analyses showed a favourable prognostic significance of Caveolin-1 expression in terms of relapse-free survival (HR=0.14; 95% CI=0.03 to 0.63) and overall survival (HR=0.29; 95% CI=0.11 to 0.74), even after adjusting for the mutational subgroup (relapse-free survival: HR=0.14, 95% CI=0.04 to 0.44; overall survival: HR=0.29, 95% CI=0.11 to 0.51) and imatinib treatment (relapse-free survival: HR=0.14, 95% CI=0.02 to 0.81; overall survival: HR=0.29, 95% CI=0.17 to 0.48).

Conclusion: Caveolin-1 represents a novel prognostic marker in gastrointestinal stromal tumours. Further studies are warranted to validate these results and to explore the mechanisms linking Caveolin-1 expression with the oncogenic pathway.
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http://dx.doi.org/10.1136/jclinpath-2021-207595DOI Listing
June 2021

HLA-DRB1 mismatch-based identification of donor-derived cell free DNA (dd-cfDNA) as a marker of rejection in heart transplant recipients: A single-institution pilot study.

J Heart Lung Transplant 2021 08 14;40(8):794-804. Epub 2021 May 14.

Department of Medical Sciences, University of Turin, Turin, Italy; Immunogenetics and Transplant Biology Service, Città della Salute e della Scienza University Hospital, Turin, Italy.

Background: Donor-derived cell-free DNA (dd-cfDNA) is considered a reliable marker of organ damage with potential applications in the follow-up of transplant recipients.

Methods: In this work we present an assay based on the donor-recipient HLA-mismatch (human leukocyte antigen) at the HLA-DRB1 locus to monitor rejection by quantifying the percentage of dd-cfDNA using a droplet digital PCR (polymerase chain reaction) technique. A panel of probes targeting the HLA-DRB1 locus and covering >85% genetic variability was validated and used to assess dd-cfDNA levels in a prospective cohort of 19 adult heart transplant recipients (mean age 50.9±14.8 years). The assay was carried out on a total of 232 liquid biopsies collected at the same time as endomyocardial biopsy (EMB) during routine post-transplant follow-up.

Results: Results show a significant increase of dd-cfDNA related to ischemia-reperfusion injury (2.22±2.09%) and to acute cellular rejection (1.71±3.10%) compared to stable conditions (0.43±1.04%, p < 0.0001). On the contrary, no increase was observed during infections or vascular complications, underlining the potential role of this biomarker for rejection monitoring. With a cut-off of 0.11%, the test showed 70.8% specificity (95% CI, 58.17% - 81.40%) and 64.2% sensitivity (95% CI, 49.80% - 76.86%) in discriminating acute rejection from no rejection.

Conclusions: These data demonstrate that this HLA mismatch-based droplet digital PCR method is effective for monitoring rejection in heart transplant recipients. Compared to next generation sequencing approaches, it is far more flexible, less expensive and provides faster results.
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http://dx.doi.org/10.1016/j.healun.2021.05.001DOI Listing
August 2021

Adrenal Rests in the Uro-genital Tract of an Adult Population.

Endocr Pathol 2021 Sep 7;32(3):375-384. Epub 2021 Jun 7.

Pathology Unit, Department of Oncology, Città Della Salute E Della Scienza Hospital, University of Turin, Turin, Italy.

Ectopic adrenal rests are a rare condition which can be found in various sites, generally in the retroperitoneum or pelvis along the path of gonadal descent. Their real prevalence is unknown. Males are more commonly affected, at least in the pediatric age. Adrenal rests are usually clinically silent and incidentally found in surgical samples, mostly in the pediatric population, and rarely in adults. With the aim of increasing knowledge and estimating the prevalence of ectopic adrenocortical tissue in the adult population, 44 adrenal rests in the urogenital tract of 40 adults are described. These represent approximately 0.07% of the total number of urogenital and gynecological surgeries performed in the 22 considered years. Adrenal rests were identified in the spermatic cord (10 males) and in paraovarian, parasalpingeal, or infundibulopelvic ligament locations (30 females). All but one was incidental findings. One case regarded an adrenocortical carcinoma arisen in adrenal rests. A literature review of adrenal ectopia in the urogenital tract of adults identified 57 reported cases from 53 patients, with similar clinicopathological features as those of our series, with the exception of a lower incidence of parasalpingeal locations. Despite their limited clinical implications, awareness of ectopic adrenal rests is essential also in adults for at least two reasons: (a) to correctly identify sources of adrenocortical hormone production in case of adrenal insufficiency or hormonal imbalance and (b) to avoid misinterpretations in the diagnostic workup of renal cell carcinoma, adrenocortical tumors, and rare gonadal neoplasms, including Sertoli/Leydig cell tumors.
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http://dx.doi.org/10.1007/s12022-021-09685-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370964PMC
September 2021

Predictor Analysis in Radiofrequency Ablation of Benign Thyroid Nodules: A Single Center Experience.

Front Endocrinol (Lausanne) 2021 17;12:638880. Epub 2021 May 17.

Division of Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy.

Purpose: To confirm the efficacy of ultrasound (US) guided radiofrequency ablation (RFA) in the treatment of benign thyroid nodules, we evaluated as primary outcome the technical efficacy and clinical success in a single center dataset. The secondary outcome was to find a correlation between nodules' pre-treatment features and volume reduction rate (VRR) ≥75% at 12 months after RFA and during follow-up period.

Methods: This retrospective study included 119 consecutive patients (99 females, 20 males, 51.5 ± 14.4 years) with benign thyroid nodules treated in our hospital between October 2014 and December 2018 with a mean follow-up of 26.8 months (range 3-48). Clinical and US features before and after RFA were evaluated by a US examination at 1, 3, 6, 12 months and annually thereafter up to 48 months.

Results: The median pre-treatment volume was 22.4 ml; after RFA we observed a statistically significant volume reduction from the first month (11.7 ml) to the last follow-up (p < 0.001 for all follow-up times). The median VRR was 47.1, 55.3, 61.2, 67.6, 72.8, 71.3, and 62.9% at 1, 3, 6, 12, 24, 36, and 48 months of follow-up respectively, showing a progressive significant improvement up to 24 months (VRRs 1 3 months, 3 6 months and 6 12 months p < 0.001, 12 24 months p = 0.05) while no differences at 24 36 and 36 48 months were observed. Symptoms improved significantly (complete resolution 64.35%, partial resolution 35.65%), and neck circumference was reduced as compared to pre-treatment (p < 0.001). Lower pre-treatment neck circumference (37.5 36.0 cm, p = 0.01) was a positive predictor of VRR ≥75% at 12 months. Macrocystic echostructure (HR 2.48, p 0.046) and pre-treatment volume >22.4 ml (HR 0.54, p 0.036) were found to be independent positive and negative predictors of VRR ≥75% respectively. One-month post RFA VRR ≥50% represented the best positive predictor of technical success.

Conclusions: This study confirmed the efficacy of RFA in the treatment of benign thyroid nodules. In particular we show that by selecting macrocystic nodules smaller than 22.4 ml better long-term response can be achieved, which is predicted by an early shrinkage of the nodule.
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http://dx.doi.org/10.3389/fendo.2021.638880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165384PMC
May 2021

Pathological Characterization of Tumor Immune Microenvironment (TIME) in Malignant Pleural Mesothelioma.

Cancers (Basel) 2021 May 24;13(11). Epub 2021 May 24.

Department of Oncology, University of Turin, 10043 Orbassano, Italy.

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive disease that arises from pleural mesothelial cells, characterized by a median survival of approximately 13-15 months after diagnosis. The primary cause of this disease is asbestos exposure and the main issues associated with it are late diagnosis and lack of effective therapies. Asbestos-induced cellular damage is associated with the generation of an inflammatory microenvironment that influences and supports tumor growth, possibly in association with patients' genetic predisposition and tumor genomic profile. The chronic inflammatory response to asbestos fibers leads to a unique tumor immune microenvironment (TIME) composed of a heterogeneous mixture of stromal, endothelial, and immune cells, and relative composition and interaction among them is suggested to bear prognostic and therapeutic implications. TIME in MPM is known to be constituted by immunosuppressive cells, such as type 2 tumor-associated macrophages and T regulatory lymphocytes, plus the expression of several immunosuppressive factors, such as tumor-associated PD-L1. Several studies in recent years have contributed to achieve a greater understanding of the pathogenetic mechanisms in tumor development and pathobiology of TIME, that opens the way to new therapeutic strategies. The study of TIME is fundamental in identifying appropriate prognostic and predictive tissue biomarkers. In the present review, we summarize the current knowledge about the pathological characterization of TIME in MPM.
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http://dx.doi.org/10.3390/cancers13112564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197227PMC
May 2021

Differential Expression Profiles of Cell-to-Matrix-Related Molecules in Adrenal Cortical Tumors: Diagnostic and Prognostic Implications.

J Pers Med 2021 May 6;11(5). Epub 2021 May 6.

Department of Oncology, Città della Salute e della Scienza, University of Turin, 10126 Turin, Italy.

The molecular mechanisms of adrenocortical carcinoma development are incompletely defined. De-regulation of cellular-to-extracellular matrix interactions and angiogenesis appear among mechanisms associated to the malignant phenotype. Our aim was to investigate, employing PCR-based array profiling, 157 molecules involved in cell-to-matrix interactions and angiogenesis in a frozen series of 6 benign and 6 malignant adrenocortical neoplasms, to identify novel pathogenetic markers. In 14 genes, a significant dysregulation was detected in adrenocortical carcinomas as compared to adenomas, most of them being downregulated. Three exceptions-hyaluronan synthase 1 (HAS-1), laminin α3 and osteopontin genes-demonstrated an increased expression in adrenocortical carcinomas of 4.46, 4.23 and 20.32-fold, respectively, and were validated by immunohistochemistry on a series of paraffin-embedded tissues, including 20 adenomas and 73 carcinomas. Osteopontin protein, absent in all adenomas, was expressed in a carcinoma subset (25/73) ( = 0.0022). Laminin α3 and HAS-1 were mostly expressed in smooth muscle and endothelial cells of the vascular network of both benign and malignant adrenocortical tumors. HAS-1 was also detected in tumor cells, with a more intense pattern in carcinomas. In this group, strong expression was significantly associated with more favorable clinicopathological features. These data demonstrate that cell-to-matrix interactions are specifically altered in adrenocortical carcinoma and identify osteopontin and HAS-1 as novel potential diagnostic and prognostic biomarkers, respectively, in adrenal cortical tumors.
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http://dx.doi.org/10.3390/jpm11050378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148197PMC
May 2021

Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma.

Cancers (Basel) 2021 May 12;13(10). Epub 2021 May 12.

Department of Oncology, University of Torino, 10043 Orbassano, Italy.

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer generally diagnosed at an advanced stage and characterized by a poor prognosis. The absence of alterations in druggable kinases, together with an immune-suppressive tumor microenvironment, limits the use of molecular targeted therapies, making the treatment of MPM particularly challenging. Here we investigated the in vitro susceptibility of MPM to lurbinectedin (PM01183), a marine-derived drug that recently received accelerated approval by the FDA for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy.

Methods: A panel of primary MPM cultures, resembling the three major MPM histological subtypes (epithelioid, sarcomatoid, and biphasic), was characterized in terms of BAP1 status and histological markers. Subsequently, we explored the effects of lurbinectedin at nanomolar concentration on cell cycle, cell viability, DNA damage, genotoxic stress response, and proliferation.

Results: Stabilized MPM cultures exhibited high sensitivity to lurbinectedin independently from the BAP1 mutational status and histological classification. Specifically, we observed that lurbinectedin rapidly promoted a cell cycle arrest in the S-phase and the activation of the DNA damage response, two conditions that invariably resulted in an irreversible DNA fragmentation, together with strong apoptotic cell death. Moreover, the analysis of long-term treatment indicated that lurbinectedin severely impacts MPM transforming abilities in vitro.

Conclusion: Overall, our data provide evidence that lurbinectedin exerts a potent antitumoral activity on primary MPM cells, independently from both the histological subtype and BAP1 alteration, suggesting its potential activity in the treatment of MPM patients.
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http://dx.doi.org/10.3390/cancers13102332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151304PMC
May 2021

INSM1 Expression in Breast Neoplasms with Neuroedocrine Features.

Endocr Pathol 2021 May 19. Epub 2021 May 19.

Department of Oncology, Pathology Unit, University of Turin, Via Santena 7, 10126, Turin, Italy.

According to the 2019 WHO classification of breast tumors, neuroendocrine neoplasms (NENs) are classified into well-differentiated NE tumors (NET) and poorly differentiated NE carcinomas (NEC), while other breast cancers (BCs) of special and no special type with neuroendocrine (NE) features are not incorporated in this scheme anymore. We aimed to assess whether INSM1, a novel NE marker, could have a role in breast NEN subtyping. We selected 63 BCs operated from 2003 to 2018, classified as BCs with NE features, with available clinico-pathological data. Following 2019 WHO criteria, this cohort was reclassified into 37 NETs/NECs, the remaining 26 tumors representing solid-papillary (7), mucinous (7), and mixed type (12) carcinomas with NE differentiation. Chromogranin A (CGA) and synaptophysin (SYN) immunostains were reviewed, and INSM1 was tested by immunohistochemistry. Thirty CGA- and SYN-negative no special type BCs served as negative control. INSM1 was expressed in 52/63 cases of the whole cohort (82.54%). INSM1 positive and negative cases had no significantly different clinico-pathological characteristics. INSM1 expression was not significantly different between the newly reclassified NET/NEC group and other BCs with NE features. No immunoexpression was observed in control BCs. The sensitivity and specificity of INSM1 for the NE phenotype was 82.5% and 100%, respectively, compared to 61.9% and 100% for CGA, and 95.2 and 100% for SYN. In conclusion, INSM1 is as accurate as traditional NE biomarkers to identify NE differentiation in BC. In analogy to standard NE markers, INSM1 could not distinguish NET and NEC from the other BC histotypes with NE differentiation.
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http://dx.doi.org/10.1007/s12022-021-09682-1DOI Listing
May 2021

A hybrid deep learning approach for gland segmentation in prostate histopathological images.

Artif Intell Med 2021 05 16;115:102076. Epub 2021 Apr 16.

Politecnico di Torino, PoliTo(BIO)Med Lab, Biolab, Department of Electronics and Telecommunications, Corso Duca degli Abruzzi 24, Turin, 10129, Italy.

Background: In digital pathology, the morphology and architecture of prostate glands have been routinely adopted by pathologists to evaluate the presence of cancer tissue. The manual annotations are operator-dependent, error-prone and time-consuming. The automated segmentation of prostate glands can be very challenging too due to large appearance variation and serious degeneration of these histological structures.

Method: A new image segmentation method, called RINGS (Rapid IdentificatioN of Glandural Structures), is presented to segment prostate glands in histopathological images. We designed a novel glands segmentation strategy using a multi-channel algorithm that exploits and fuses both traditional and deep learning techniques. Specifically, the proposed approach employs a hybrid segmentation strategy based on stroma detection to accurately detect and delineate the prostate glands contours.

Results: Automated results are compared with manual annotations and seven state-of-the-art techniques designed for glands segmentation. Being based on stroma segmentation, no performance degradation is observed when segmenting healthy or pathological structures. Our method is able to delineate the prostate gland of the unknown histopathological image with a dice score of 90.16 % and outperforms all the compared state-of-the-art methods.

Conclusions: To the best of our knowledge, the RINGS algorithm is the first fully automated method capable of maintaining a high sensitivity even in the presence of severe glandular degeneration. The proposed method will help to detect the prostate glands accurately and assist the pathologists to make accurate diagnosis and treatment. The developed model can be used to support prostate cancer diagnosis in polyclinics and community care centres.
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http://dx.doi.org/10.1016/j.artmed.2021.102076DOI Listing
May 2021

Automated assessment of glomerulosclerosis and tubular atrophy using deep learning.

Comput Med Imaging Graph 2021 06 2;90:101930. Epub 2021 May 2.

Politecnico di Torino, PoliToBIOMed Lab, Biolab, Department of Electronics and Telecommunications, Corso Duca degli Abruzzi 24, Turin, 10129, Italy.

In kidney transplantations, pathologists evaluate the architecture of both glomeruli, interstitium and tubules to assess the nephron status. An accurate assessment of glomerulosclerosis and tubular atrophy is crucial for determining kidney acceptance, which is currently based on the pathologists' histological evaluations on renal biopsies in addition to clinical data. In this work, we present an automated algorithm, called RENTAG (Robust EvaluatioN of Tubular Atrophy & Glomerulosclerosis), for the segmentation and classification of glomerular and tubular structures in histopathological images. The proposed novel strategy combines the accuracy of a level-set with the semantic segmentation of convolutional neural networks to detect the glomeruli and tubules contours. In the TEST set, our method exhibited excellent performance in both glomeruli (dice score: 0.9529) and tubule (dice score: 0.9174) detection and outperformed all the compared methods. To the best of our knowledge, the RENTAG algorithm is the first fully automated method capable of quantifying glomerulosclerosis and tubular atrophy in digital histological images. The developed software can be employed for the analysis of pre-transplantation biopsies to support the pathologists' diagnostic activity.
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http://dx.doi.org/10.1016/j.compmedimag.2021.101930DOI Listing
June 2021

Placenta histopathology in SARS-CoV-2 infection: analysis of a consecutive series and comparison with control cohorts.

Virchows Arch 2021 Oct 1;479(4):715-728. Epub 2021 May 1.

Obstetrics and Gynecology 1U, Department of Surgical Sciences, Sant'Anna Hospital, University of Turin and "Città della Salute e della Scienza di Torino" University Hospital, Turin, Italy.

Infection by SARS-CoV-2 has been shown to involve a wide range of organs and tissues, leading to a kaleidoscope of clinical conditions. Within this spectrum, an involvement of the fetal-maternal unit could be expected, but, so far, the histopathological evaluation of placentas delivered by women with SARS-CoV-2 infection did not show distinct hallmarks. A consecutive series of 11 placentas, delivered by 10 women with COVID-19 admitted to our Obstetrics and Gynecology clinic have been investigated and compared to a control cohort of 58 pre-COVID-19 placentas and 28 placentas delivered by women who had a previous cesarean section. Four out of eleven placentas showed changes consistent with chronic villitis/villitis of unknown etiology (VUE), while in one case, chronic histiocytic intervillositis was diagnosed. Thrombo-hemorrhagic alterations were observed in a subset of cases. Compared to the control cohort, chronic villitis/VUE (p < 0.001), chronic deciduitis (p = 0.023), microvascular thrombosis (p = 0.003), presence of infarction areas (p = 0.047) and of accelerated villous maturation (p = 0.005) showed higher frequencies in placentas delivered by women with COVID-19. Chronic villitis/VUE (p = 0.003) and accelerated villous maturation (p = 0.019) remained statistically significant by restricting the analysis to placentas delivered after a previous cesarean section. The observed differences in terms of pathological findings could be consistent with SARS-CoV-2 pathogenesis, but just a subset of alterations remained statistically significant after adjusting for a previous cesarean section. A careful consideration of potential confounders is warranted in future studies exploring the relationship between COVID-19 and pregnancy.
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http://dx.doi.org/10.1007/s00428-021-03097-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088311PMC
October 2021

Intron 4-5 hTERT DNA Hypermethylation in Merkel Cell Carcinoma: Frequency, Association with Other Clinico-pathological Features and Prognostic Relevance.

Endocr Pathol 2021 Sep 28;32(3):385-395. Epub 2021 Apr 28.

Department of Biomedical and Neuromotor Sciences (DIBINEM) Surgical Pathology Section- Alma Mater Studiorum , University of Bologna , Bologna, Italy.

Merkel cell carcinoma (MCC) is an aggressive skin tumor with neuroendocrine differentiation, mainly affecting elderly population or immunocompromised individuals. As methylation of the human telomerase reverse transcriptase (mhTERT) has been shown to be a prognostic factor in different tumors, we investigated its role in MCC, in particular in intron 4-5 where rs10069690 has been mapped and recognized as a cancer susceptibility locus. DNA methylation analysis of hTERT gene was assessed retrospectively in a cohort of 69 MCC patients from the University of Bologna, University of Turin and University of Insubria. Overall mortality was evaluated with Kaplan-Meier curves and multivariable Royston-Parmar models. High levels of mhTERT (mhTERT) (HR = 2.500, p = 0.015) and p63 (HR = 2.659, p = 0.016) were the only two clinico-pathological features significantly associated with a higher overall mortality at the multivariate analysis. We did not find different levels of mhTERT between MCPyV (+) and (-) cases (21 vs 14, p = 0.554); furthermore, mhTERT was strongly associated with older age (80.5 vs 72 years, p = 0.026), no angioinvasion (40.7% vs 71.0%, p = 0.015), lower Ki67 (50 vs 70%, p = 0.005), and PD-L1 expressions in both tumor (0 vs 3%, p = 0.021) and immune cells (0 vs 10%, p = 0.002). mhTERT is a frequently involved epigenetic mechanism and a relevant prognostic factor in MCC. In addition, it belongs to the shared oncogenic pathways of MCC (MCPyV and UV-radiations) and it could be crucial, together with other epigenetic and genetic mechanisms as gene amplification, in determining the final levels of hTERT mRNA and telomerase activity in these patients.
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http://dx.doi.org/10.1007/s12022-021-09669-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370894PMC
September 2021

SMARCA2 Deficiency While Preserving SMARCA4 and SMARCB1 in Lung Neuroendocrine Carcinomas.

J Thorac Oncol 2021 05;16(5):e32-e35

Inter-Hospital Pathology Division, IRCCS MultiMedica, Milan, Italy, Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2021.01.1613DOI Listing
May 2021

DNA Methylation Profiling Discriminates between Malignant Pleural Mesothelioma and Neoplastic or Reactive Histologic Mimics.

J Mol Diagn 2021 07 20;23(7):834-846. Epub 2021 Apr 20.

Department of Neuropathology, Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

The diagnosis of malignant pleural mesothelioma (MPM) is challenging because of its potential overlap with other neoplasms or even with reactive conditions. DNA methylation analysis is effective in diagnosing tumors. In the present study, this approach was tested for use in MPM diagnosis. The DNA methylation patterns of a discovery cohort and an independent-validation cohort of MPMs were compared to those of 202 cases representing malignant and benign diagnostic mimics (angiosarcoma, desmoid-type fibromatosis, epithelioid sarcoma, leiomyosarcoma, lung adenocarcinoma, lung squamous cell carcinoma, melanoma, nodular fasciitis, reactive mesothelial hyperplasia, sclerosing fibrous pleuritis, solitary fibrous tumor, and synovial sarcoma). By both unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis, MPM samples in the discovery cohort exhibited a DNA methylation profile different from those of other neoplastic and reactive mimics. These results were confirmed in the independent validation cohort and by in silico analysis of the MPM-The Cancer Genome Atlas data set. Copy number variation profiles were also inferred to identify molecular hallmarks of MPM, including CDKN2A and NF2 deletions. Methylation profiling was effective in the diagnosis of MPM, although caution is advised in samples with low tumor cell content.
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http://dx.doi.org/10.1016/j.jmoldx.2021.04.002DOI Listing
July 2021

Radiofrequency Thermal Ablation for a Small Papillary Thyroid Carcinoma in a Patient Unfit for Surgery: A Case Report.

Front Endocrinol (Lausanne) 2021 29;12:566362. Epub 2021 Mar 29.

Pathology Unit, Department of Oncology, University of Turin, Turin, Italy.

Ultrasound-guided radiofrequency thermal ablation has been proposed as an effective and safe procedure for treating patients who have low-risk papillary thyroid microcarcinomas and/or are unfit for surgery. We present the case of a 72-year old male patient with a small thyroid nodule diagnosed as papillary carcinoma after fine needle aspiration. Since the patient had other serious comorbidities, priority was given to other therapies and the malignant thyroid nodule was submitted to active surveillance. After detecting at a follow-up examination a slight dimensional increase of the nodule, the possibility of a radiofrequency thermal ablation was proposed to our patient, who accepted. The procedure was safely and effectively carried out. Follow-up examinations with ultrasonography (or contrast enhanced ultrasound), conducted after 1, 3, 6, and 12 months, demonstrated a progressive reduction of size and loss of vascularization in the treated area. The fine needle aspiration was repeated after 6 months: the sample revealed a very poor cellularity composed of inflammatory cells and thick colloid; no residual neoplastic cells were observed. Our experience confirmed what already demonstrated by previous reports: radiofrequency ablation can effectively eliminate small papillary carcinomas, with a very low complication rate. It may be an alternative strategy for the treatment of low-risk, indolent papillary thyroid microcarcinomas, thus avoiding the potential side-effects of surgery in patients at risk for relevant comorbidities.
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http://dx.doi.org/10.3389/fendo.2021.566362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040516PMC
March 2021

Recent advances and current controversies in lung neuroendocrine neoplasms.

Semin Diagn Pathol 2021 Sep 19;38(5):90-97. Epub 2021 Mar 19.

Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Inter-Hospital Pathology Division, IRCCS MultiMedica, Milan, Italy. Electronic address:

In the lung, neuroendocrine tumors (NETs), namely typical and atypical carcinoids, and neuroendocrine carcinomas (NECs), grouping small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), make up for distinct tumor entities according to epidemiological, genetic, pathologic and clinical data. The proper classification is essential in clinical practice for diagnosis, prognosis and therapy purposes. Through an extensive literature survey, three perspectives on lung NENs have been revised: i) criteria and terminology on biopsy or cytology samples of primaries or metastases; ii) carcinoids with elevated mitotic counts and/or Ki-67 proliferation rates; iii) relevance of molecular landscape to identify new tumor entities and therapeutic targets. Furthermore, a dispute about lung NEN development has been raised according to emerging molecular models. We herein provide a pathology update on practical topics in the setting of lung NENs according to the current classification (recent advances). We have also reappraised the development of these tumors by modeling risk factors and natural history of disease (recent controversies). Combining recent advances and controversies may help clarify our biological understanding of lung NENs and give practical information for the clinical decision-making process.
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http://dx.doi.org/10.1053/j.semdp.2021.03.002DOI Listing
September 2021

Diagnostic Value of Conventional PET Parameters and Radiomic Features Extracted from 18F-FDG-PET/CT for Histologic Subtype Classification and Characterization of Lung Neuroendocrine Neoplasms.

Biomedicines 2021 Mar 10;9(3). Epub 2021 Mar 10.

Nuclear Medicine Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy.

Aim: To evaluate if conventional Positron emission tomography (PET) parameters and radiomic features (RFs) extracted by 18F-FDG-PET/CT can differentiate among different histological subtypes of lung neuroendocrine neoplasms (Lu-NENs).

Methods: Forty-four naïve-treatment patients on whom 18F-FDG-PET/CT was performed for histologically confirmed Lu-NEN (n = 46) were retrospectively included. Manual segmentation was performed by two operators allowing for extraction of four conventional PET parameters (SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG)) and 41 RFs. Lu-NENs were classified into two groups: lung neuroendocrine tumors (Lu-NETs) vs. lung neuroendocrine carcinomas (Lu-NECs). Lu-NETs were classified according to histological subtypes (typical (TC)/atypical carcinoid (AC)), Ki67-level, and TNM staging. The least absolute shrink age and selection operator (LASSO) method was used to select the most predictive RFs for classification and Pearson correlation analysis was performed between conventional PET parameters and selected RFs.

Results: PET parameters, in particular, SUVmax (area under the curve (AUC) = 0.91; cut-off = 5.16) were higher in Lu-NECs vs. Lu-NETs ( < 0.001). Among RFs, HISTO_Entropy_log10 was the most predictive (AUC = 0.90), but correlated with SUVmax/SUVmean (r = 0.95/r = 0.94, respectively). No statistical differences were found between conventional PET parameters and RFs ( > 0.05) and TC vs. AC classification. Conventional PET parameters were correlated with N+ status in Lu-NETs.

Conclusion: In our study, conventional PET parameters were able to distinguish Lu-NECs from Lu-NETs, but not TC from AC. RFs did not provide additional information.
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http://dx.doi.org/10.3390/biomedicines9030281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001140PMC
March 2021

Protective Role of the M-Sec-Tunneling Nanotube System in Podocytes.

J Am Soc Nephrol 2021 05 15;32(5):1114-1130. Epub 2021 Mar 15.

Department of Medical Sciences, University of Turin, Turin, Italy.

Background: Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored.

Methods: We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy).

Results: Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. , M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury.

Conclusions: These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued TNT-mediated horizontal transfer may open new avenues of research.
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http://dx.doi.org/10.1681/ASN.2020071076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259684PMC
May 2021

Neuroendocrine neoplasms of the appendix, colon and rectum.

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

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

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

The International Association for the Study of Lung Cancer Global Survey on Programmed Death-Ligand 1 Testing for NSCLC.

J Thorac Oncol 2021 04 2;16(4):686-696. Epub 2021 Mar 2.

Carolinas Pathology Group, Charlotte, North Carolina.

Introduction: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is required to determine the eligibility for pembrolizumab monotherapy in advanced NSCLC worldwide and for several other indications depending on the country. Four assays have been approved/ Communauté Européene-In vitro Diagnostic (CV-IVD)-marked, but PD-L1 IHC seems diversely implemented across regions and laboratories with the application of laboratory-developed tests (LDTs).

Method: To assess the practice of PD-L1 IHC and identify issues and disparities, the International Association for the Study of Lung Cancer Pathology Committee conducted a global survey for pathologists from January to May 2019, comprising multiple questions on preanalytical, analytical, and postanalytical conditions.

Result: A total of 344 pathologists from 64 countries participated with 41% from Europe, 24% from North America, and 18% from Asia. Besides biopsies and resections, cellblocks were used by 75% of the participants and smears by 11%. The clone 22C3 was most often used (69%) followed by SP263 (51%). They were applied as an LDT by 40% and 30% of the users, respectively, and 76% of the participants developed at least one LDT. Half of the participants reported a turnaround time of less than or equal to 2 days, whereas 13% reported that of greater than or equal to 5 days. In addition, quality assurance (QA), formal training for scoring, and standardized reporting were not implemented by 18%, 16%, and 14% of the participants, respectively.

Conclusions: Heterogeneity in PD-L1 testing is marked across regions and laboratories in terms of antibody clones, IHC assays, samples, turnaround times, and QA measures. The lack of QA, formal training, and standardized reporting stated by a considerable minority identifies a need for additional QA measures and training opportunities.
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http://dx.doi.org/10.1016/j.jtho.2020.12.026DOI Listing
April 2021

Molecular Pathology of Poorly Differentiated and Anaplastic Thyroid Cancer: What Do Pathologists Need to Know?

Endocr Pathol 2021 Mar 4;32(1):63-76. Epub 2021 Feb 4.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna School of Medicine, Bologna, Italy.

The molecular characterization of poorly and anaplastic thyroid carcinomas has been greatly improved in the last years following the advent of high throughput technologies. However, with special reference to genomic data, the prevalence of reported alterations is partly affected by classification criteria. The impact of molecular pathology in these tumors is multifaceted and bears diagnostic, prognostic, and predictive implications although its use in the clinical practice is not completely assessed. Genomic profiling data claim that genetic alterations in poorly differentiated and anaplastic thyroid carcinomas include "Early" and "Late" molecular events, which are consistent with a multi-step model of progression. "Early" driver events are mostly RAS and BRAF mutations, whereas "Late" changes include above all TP53 and TERT promoter mutations, as well as dysregulation of gene involved in the cell cycle, chromatin remodeling, histone modifications, and DNA mismatch repair. Gene fusions are rare but represent relevant therapeutic targets. Epigenetic modifications are also playing a relevant role in poorly differentiated and anaplastic thyroid carcinomas, with altered regulation of either genes by methylation/deacetylation or non-coding RNAs. The biological effects of epigenetic modifications are not fully elucidated but interfere with a wide spectrum of cellular functions. From a clinical standpoint, the combination of genomic and epigenetic data shows that several molecular alterations affect druggable cellular pathways in poorly differentiated and anaplastic thyroid carcinomas, although the clinical impact of molecular typing of these tumors in terms of predictive biomarker testing is still under exploration.
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http://dx.doi.org/10.1007/s12022-021-09665-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960587PMC
March 2021

Molecular profiling of advanced non-small cell lung cancer in the era of immunotherapy approach: a multicenter Italian observational prospective study of biomarker screening in daily clinical practice.

J Clin Pathol 2021 Jan 28. Epub 2021 Jan 28.

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

Aims: Heterogeneous implementation of molecular tests in current diagnostic algorithm at a European and international level is emerging as a major issue for efficient lung cancer molecular profiling.

Methods: From May 2017 until October 2017, N=1612 patients referring to 13 Italian institutions were selected, at advanced stage non-small cell lung cancer (NSCLC), and prospectively evaluated. Principal endpoints were: the percentage of diagnoses performed on cytological and histological material, the proportion of requests for epidermal growth factor receptor (EGFR) mutational status, and resistance mutations detected on tissue and/or liquid biopsy samples after first-generation or second-generation tyrosine kinase inhibitors, the proportion of requests for anaplastic lymphoma kinase (ALK) gene rearrangements, ROS proto-oncogene 1 (ROS1) and Kirsten Rat Sarcoma (KRAS) determinations, the proportion of requests for programmed death-ligand1 (PD-L1) evaluation and, finally, the different assays used for the detection of EGFR mutations, ALK and ROS1 gene rearrangements and PD-L1 expression.

Results: Of 1325 patients finally included, only 50.8% requests were related to driver mutations with target agents already available in first-line at that preplanned time, while 49.2% were associated with PD-L1, ROS1, KRAS and others. Multiplex genomic assays (such as next-generation sequencing) were considered by all participating centres.

Conclusions: To the best of our knowledge, this is the first study in a 'real-life daily practice' involving both pathologists and oncologists evaluating routinely workflow and trends towards improvements in molecular requests. Collected data aim to describe the applied algorithms and evolution of molecular screening for stage IV NSCLC in clinical practice.
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http://dx.doi.org/10.1136/jclinpath-2020-207339DOI Listing
January 2021

Morphologic and molecular classification of lung neuroendocrine neoplasms.

Virchows Arch 2021 Jan 21;478(1):5-19. Epub 2021 Jan 21.

Inter-Hospital Pathology Division, Servizio Interaziendale di Anatomia Patologica, IRCCS MultiMedica, Via Gaudenzio Fantoli 16/15, 20138, Milan, Italy.

Neuroendocrine neoplasms (NENs) of the lung encompass neuroendocrine tumors (NETs) composed of typical (TC) and atypical (AC) carcinoids and full-fledged carcinomas (NECs) inclusive of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). NETs and NECs are thought to represent distinct and separate lesions with neither molecular overlap nor common developmental continuum. Two perspectives were addressed regarding the morphologic and molecular classification of lung NENs: (i) a supervised approach by browsing the traditional classification, the relevant gene alterations, and their clinical implications; and (ii) an unsupervised approach, by reappraising neoplasms according to risk factors and natural history of disease to construct an interpretation model relied on biological data. We herein emphasize lights and shadows of the current classification of lung NENs and provide an alternative outlook on these tumors focused on what we currently know about the biological determinants and the natural history of disease.
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http://dx.doi.org/10.1007/s00428-020-03015-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966641PMC
January 2021

A Subset of Large Cell Neuroendocrine Carcinomas in the Gastroenteropancreatic Tract May Evolve from Pre-existing Well-Differentiated Neuroendocrine Tumors.

Endocr Pathol 2021 Sep 12;32(3):396-407. Epub 2021 Jan 12.

Department of Medical Oncology, Fox Chase Cancer Centre, Philadelphia, PA, USA.

In the gastro-entero-pancreatic (GEP) tract, neuroendocrine neoplasms (NENs) include well differentiated neuroendocrine tumors (NETs) and high-grade NE carcinomas (NECs), which are thought to make up separate and mutually exclusive tumor entities. Little is known, however, as to whether there may be any pathogenetic link between them. Clustering analysis of a 10-gene panel generated from a previously reported next-generation sequencing analysis on 48 GEP-NENs with clinical annotations was used in the study. Unsupervised cluster analysis showed three histology-independent clusters, namely, C1, C2, and C3, which accounted for 44% of patients but the entire array of mutations. All but two NECs fell into the clusters, yet with different prevalence rates (p < 0.0001). A model was devised according to which NETs were likely to evolve into NECs upon progression of C3 into C1 and C2, despite different morphology. The median Ki-67 labeling index was 5% in C3 showing better prognosis and 50% in C1 and C2 experiencing worse prognosis, with an impressive intra-tumor heterogeneity of diversely proliferating tumor areas. This study suggests that a subset of large cell NECs in the gastroenteropancreatic tract may evolve from pre-existing well-differentiated NETs.
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http://dx.doi.org/10.1007/s12022-020-09659-6DOI Listing
September 2021

Genomics of High-Grade Neuroendocrine Neoplasms: Well-Differentiated Neuroendocrine Tumor with High-Grade Features (G3 NET) and Neuroendocrine Carcinomas (NEC) of Various Anatomic Sites.

Endocr Pathol 2021 Mar 12;32(1):192-210. Epub 2021 Jan 12.

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

High-grade neuroendocrine neoplasms (HG-NENs) are clinically aggressive diseases, the classification of which has recently been redefined. They now include both poorly differentiated NENs (neuroendocrine carcinoma, NECs) and high proliferating well-differentiated NENs (called grade 3 neuroendocrine tumors, G3 NETs, in the digestive system). In the last decade, the "molecular revolution" that has affected all fields of medical oncology has also shed light in the understanding of HG NENs heterogeneity and has provided new diagnostic and therapeutic tools, useful in the management of these malignancies. Considering the kaleidoscopic aspects of HG NENs in various anatomical sites, this review systematically addresses the genomic landscape of such neoplasm throughout the more common thoracic and digestive locations, as well as it will consider other rare but not exceptional primary sites, including the skin, the head and neck, and the urogenital system. The revision of the available literature will then be oriented to understand the translational relevance of molecular data, by analyzing conceptual issues, clinicopathological correlations, and unmet needs in this field.
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http://dx.doi.org/10.1007/s12022-020-09660-zDOI Listing
March 2021
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