Search

The tall-cell variant of papillary thyroid carcinoma (TCPTC) is the most common aggressive variant of papillary thyroid carcinoma (PTC) and typically occurs in older patients. In this study, we analyzed retrospectively the largest mono-institutional series of PTCs with tall-cell features (989 patients) over a 17-year period, re-evaluating tumors based on age at presentation and outcomes in different age groups. We divided patients into three age groups following different criteria (the criterion from the American Joint Committee on Cancer Tumor Node Metastasis (AJCC TNM) guidelines, criterion for the statistical division into tertiles and adolescent/post-adolescent criterion) to analyze the clinicopathological characteristics in different age groups, especially in terms of recurrence-free survival (RFS) and distant recurrence-free survival (DRFS). We obtained three main results: 1. the population is distributed among the different age groups, and therefore, this type of cancer is not exclusively found among those of an older age; 2. in the RFS analysis, we can see a higher probability of local recurrence in the younger and older groups and, unexpectedly, a lower probability of local recurrence in the "median age" group; and 3. in the DRFS analysis, we can observe a higher probability of distant recurrence in older patients. From a molecular perspective, no significant differences in the mutational status of BRAF were detected according to different age groups, while mutations in the TERT promoter were exclusively present in older patients of all age groups, highlighting the potential prognostic implications of TERT promoter mutations in PTCs. In conclusion, the results of this series confirm that TC morphology alone in PTCs does not have the same negative prognostic significance in the younger population as in the older population. The reason for these different outcomes remains unclear and needs further studies.

Background: Tumor immune cells influence the efficacy of immune-checkpoint inhibitors (ICIs) and many efforts aim at identifying features of tumor immune microenvironment able to predict benefit from ICIs in proficient mismatch repair (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer (mCRC)., Methods: We characterized tumor immune cell infiltrate, by assessing tumor-infiltrating lymphocytes (TILs), Immunoscore, Immunoscore-IC, and programmed death ligand-1 (PD-L1) expression in tumor samples of patients with mCRC enrolled in the AtezoTRIBE study, a phase II randomized trial comparing FOLFOXIRI/bevacizumab/atezolizumab to FOLFOXIRI/bevacizumab, with the aim of evaluating the prognostic and predictive value of these features., Results: Out of 218 patients enrolled, 181 (83%), 77 (35%), 157 (72%) and 162 (74%) specimens were successfully tested for TILs, Immunoscore, Immunoscore-IC and PD-L1 expression, respectively, and 69 (38%), 45 (58%), 50 (32%) and 21 (13%) tumors were classified as TILs-high, Immunoscore-high, Immunoscore-IC-high and PD-L1-high, respectively. A poor agreement was observed between TILs and Immunoscore or Immunoscore-IC (K of Cohen <0.20). In the pMMR population, longer progression-free survival (PFS) was reported for Immunoscore-high and Immunoscore-IC-high groups compared with Immunoscore-low (16.4 vs 12.2 months; HR: 0.55, 95% CI: 0.30 to 0.99; p=0.049) and Immunoscore-IC-low (14.8 vs 11.5 months; HR: 0.55, 95% CI: 0.35 to 0.85; p=0.007), respectively, with a significant interaction effect between treatment arms and Immunoscore-IC (p for interaction: 0.006) and a trend for Immunoscore (p for interaction: 0.13). No PFS difference was shown according to TILs and PD-L1 expression. Consistent results were reported in the overall population., Conclusions: The digital evaluation of tumor immune cell infiltrate by means of Immunoscore-IC or Immunoscore identifies the subset of patients with pMMR mCRC achieving more benefit from the addition of the anti-PD-L1 to the upfront treatment. Immunoscore-IC stands as the most promising predictor of benefit from ICIs., Competing Interests: Competing interests: AC, AK, JF: are Veracyte employees. JG: has patents associated with the immune prognostic and predictive biomarkers, is co-founder of HalioDx, a Veracyte company. SL: has a consulting or an advisory role for Amgen, Merck Serono, Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, BMS, Servier, and MSD; has received research funding from Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and BMS; and has received speakers’ fees from Roche, Lilly, BMS, Servier, Merck Serono, Pierre-Fabre, GlaxoSmithKline, and Amgen. FP: honoraria from Amgen, Bayer, Servier, Merck-Serono, Lilly, MSD, Organon, BMS, AstraZeneca, Pierre-Fabre; research grants from Bristol-Myers Squibb, AstraZeneca, Agenus and Incyte. LS: speakers’ and consultant’s fee from MSD, AstraZeneca, Servier, Bayer, Merck, Amgen, Pierre-Fabre. GM: received speakers’ fees—Merck, Amgen. CC: honoraria—Amgen, Bayer, Merck, Roche and Servier. Consulting or advisory role—Amgen, Bayer, MSD, Roche. Speakers’ Bureau—Servier. Research funding—Bayer, Merck, Servier. Travel, accommodations and expenses—Roche and Servier. All other authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Infection by SARS-CoV-2 may be associated with testicular dysfunction that could affect male fertility., Objective: Testicles of fatal COVID-19 cases were investigated to detect virus in tissue and to evaluate histopathological and transcriptomic changes., Methods: Three groups were compared: (a) uninfected controls (subjects dying of trauma or sudden cardiac death; n = 10); (b) subjects dying of COVID-19 (virus-negative in testes; n = 15); (c) subjects dying of COVID-19 (virus-positive in testes; n = 9). SARS-CoV-2 genome and nucleocapsid antigen were probed using RT-PCR, in situ hybridization, and immunohistochemistry (IHC). Infiltrating leukocytes were typed by IHC. mRNA transcripts of immune-related and testis-specific genes were quantified using the nCounter method., Results: SARS-CoV-2 was detected in testis tissue of 9/24 (37%) COVID-19 cases accompanied by scattered T-cell and macrophage infiltrates. Size of testicles and counts of spermatogenic cells were not significantly different among groups. Analysis of mRNA transcripts showed that in virus-positive testes immune processes were activated (interferon-alpha and -gamma pathways). By contrast, transcription of 12 testis-specific genes was downregulated, independently of virus positivity in tissue. By IHC, expression of the luteinizing hormone/choriogonadotropin receptor was enhanced in virus-positive compared to virus-negative testicles, while expression of receptors for androgens and the follicle-stimulating hormone were not significantly different among groups., Conclusion: In lethal COVID-19 cases, infection of testicular cells is not uncommon. Viral infection associates with activation of interferon pathways and downregulation of testis-specific genes involved in spermatogenesis. Due to the exceedingly high numbers of infected people in the pandemic, the impact of virus on fertility should be further investigated., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Trop-2 and Nectin-4 are transmembrane proteins overexpressed in many tumours and targets of antibody-drug conjugates (ADC). In metastatic colorectal cancer (mCRC), the role of Trop-2 and Nectin-4 has been poorly investigated., Methods: Tumour samples of patients randomised in the phase III TRIBE2 were assessed for Trop-2 and Nectin-4 expression., Results: Three hundred eighty-six tumours were assessed for Trop-2 expression. 90 (23%), 115 (30%) and 181 (47%) were Trop-2 high, medium and low, respectively. Patients with low Trop-2 tumours achieved longer PFS (12 versus 9.9 months, p = 0.047) and OS (27.3 versus 21.3 months, p = 0.015) than those with high/medium Trop-2 tumours. These findings were confirmed in multivariate analysis (p = 0.022 and p = 0.023, respectively). A greater OS benefit from treatment intensification with FOLFOXIRI/bevacizumab was observed in patients with high/medium Trop-2 tumours (p-for-interaction = 0.041). Two hundred fifty-one tumours were assessed for Nectin-4 expression. Fourteen (5%), 67 (27%) and 170 (68%) were high, medium and low, respectively. No prognostic impact was observed based on Nectin-4 expression and no interaction effect was reported between Nectin-4 expression groups and treatment arm., Conclusions: In mCRC, expression levels of Trop-2 and Nectin-4 are heterogeneous, suggesting a target-driven development of anti-Trop2 and anti-Nectin-4 ADCs. Medium/high Trop-2 expression is associated with worse prognosis and higher benefit from chemotherapy intensification., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: In locally advanced gastric cancer (GC), FLOT represents the standard perioperative regimen and combination with immunotherapy is under investigation. However, the role of immune tumor microenvironment (TME) is poorly recognized in this setting. We aimed to study TME characteristics and dynamics during FLOT., Methods: Paired biopsy (PRE) and surgical (POST) samples of 25 patients treated with FLOT were prospectively analyzed. After collection of clinic-pathological data, NanoString analyses were performed. The primary objective of the study was to assess the changes induced by chemotherapy in POST compared to PRE samples., Results: The unsupervised hierarchical method analysis clearly distinguished PRE and POST samples, even though some cases showed high immune gene expression at baseline. When POST samples were compared with PRE, a differential expression in hyper-expressed gene sets related to cytotoxicity, T-cell functions, complement system, tumor necrosis factor superfamily, cell cycle, and regulation was recognized. Downstaging of the primary tumor (T-regression, measured by pathologic compared to clinical T stage) was the covariate most frequently associated with these changes. Using the immune cell profiling, cases with T-regression reported a significant increase of T, CD8+ T and B cells and a decrease in mast cells, while nonresponders demonstrated an increase of T, B, cytotoxic, and mast cells., Conclusion: Our analysis shows that FLOT significantly influences immune TME of GC. While relevant modifications preferentially occur in tumors showing primary tumor regression, response to treatment seems to be associated with a specific immune profile., (© 2023 S. Karger AG, Basel.)

Background: The Italian Consensus for the Classification and Reporting of Thyroid Cytology (ICCRTC) includes six diagnostic categories (TIR 1/1C, TIR 2, TIR 3A, TIR 3B, TIR 4, and TIR 5), each indicating a different risk of malignancy. The objective of this monocentric retrospective study was to evaluate the distribution of the ICCRTC classes at the authors' institution and assess their cytohistologic correlations., Methods: The authors retrospectively collected 37,371 consecutive cytologic reports of thyroid nodules and described the clinical-pathologic features of the different cytologic categories. The cytologic diagnoses also were compared with histologic outcomes in a subset of patients., Results: The cytologic classes were distributed as follows: nondiagnostic, 15.6%; benign, 66.5%; low-risk indeterminate, 10% (TIR 3A); high-risk indeterminate, 3.5% (TIR 3B); suspicious, 1.7%; and malignant, 2.6%. According to histology, the risk of malignancy was very high in the nondiagnostic category (29.8%), with young male patients more exposed to malignancy, and it was relatively high among benign (7.8%) and indeterminate nodules (32.5% in TIR 3A; 52.1% in TIR 3B), mainly because of the high prevalence of follicular architecture in malignant tumors. On histology, the malignancy rates were 92.4% and 99.3% for the suspicious and malignant categories, respectively; aggressive variants of papillary thyroid carcinoma were mostly diagnosed in these categories., Conclusions: In this series, nondiagnostic nodules showed high prevalence and, surprisingly, high malignancy rates. Malignant tumors with follicular architecture represented a diagnostic pitfall in benign and indeterminate nodules. The suspicious and malignant categories had high specificity for malignancy. Importantly, the ICCRTC had high reliability for identifying preoperatively aggressive histotypes of thyroid carcinoma., (© 2022 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Context: Although the majority of RET alterations are single nucleotide variants (SNV), small deletions and/or insertions have been reported at variable prevalence. No information about the efficacy of RET-specific inhibitors in patients harboring RET indels has been provided., Objective: We present an update on the prevalence of RET indels in medullary thyroid cancer (MTC) and describe the efficacy of selpercatinib in patients with advanced MTC with RET indels., Methods: The MTC tissues of 287 patients were analyzed using an Ion S5 targeted sequencing. The functional role of the reported indels have been evaluated by MutationTaster. Clinical and pathological data of MTC patients harboring a RET indel were collected and analyzed. Two patients with a RET indel were treated with selpercatinib., Results: Among 178 RET-positive cases, 147 (82.6%) harbored a SNV and 31 (17.4%) a RET in-frame indel. Nine indels were not previously reported and were found to be disease causing by MutationTaster. Patients harboring an indel were found to have an aggressive disease and 2 of them were treated with selpercatinib, experiencing a good response to the treatment., Conclusion: These data show that RET indels are not infrequent and correlate with an aggressive disease. Two RET indel-positive patients showed a partial response to the treatment with a highly selective RET inhibitor; thus, these RET indels can be considered actionable mutations. In order to not miss these alterations, the analysis of the full gene is recommended., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Immune checkpoint inhibitors have not shown clinical benefit to patients with metastatic colorectal cancer who had proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumours in previous studies. Both an active combination chemotherapy (FOLFOXIRI; fluorouracil, leucovorin, oxaliplatin, and irinotecan) and bevacizumab seem able to increase the immunogenicity of pMMR or MSS tumours. We aimed to provide preliminary evidence of benefit from the addition of the anti-PD-L1 agent atezolizumab to first-line FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer., Methods: AtezoTRIBE was a multicentre, open-label, randomised, controlled, phase 2 study of patients (aged 18-70 years with an Eastern Cooperative Oncology Group [ECOG] performance status of 0-2 and aged 71-75 years with an ECOG performance status of 0) with histologically confirmed, unresectable, previously untreated metastatic colorectal cancer and adequate organ function, who were recruited from 22 oncology centres in Italy. Patients were stratified according to centre, ECOG performance status, primary tumour site, and previous adjuvant therapy. A randomisation system incorporating a minimisation algorithm randomly assigned (1:2) patients via a masked web-based allocation procedure to two groups: the control group received first-line FOLFOXIRI (intravenous 165 mg/m 2 irinotecan, 85 mg/m 2 oxaliplatin, 200 mg/m 2 leucovorin, and 3200 mg/m 2 fluorouracil as a 48 h infusion) plus bevacizumab (5 mg/kg intravenously), and the atezolizumab group received the same regimen plus atezolizumab (840 mg intravenously). Combination treatments were administered up to eight 14-day cycles followed by maintenance with fluorouracil and leucovorin plus bevacizumab with or without atezolizumab, according to randomisation group, until disease progression, unacceptable adverse events, or consent withdrawal. The primary endpoint was progression-free survival, analysed by the intention-to-treat principle. Safety was assessed in patients who received at least one dose of the study treatment. The study recruitment is completed. The trial is registered with Clinicaltrials.gov, NCT03721653., Findings: Between Nov 30, 2018, and Feb 26, 2020, 218 patients were randomly assigned and received treatment (73 in the control group and 145 in the atezolizumab group). At the data cutoff (Aug 1, 2021), median follow-up was 19·9 months (IQR 17·3-23·9). Median progression-free survival was 13·1 months (80% CI 12·5-13·8) in the atezolizumab group and 11·5 months (10·0-12·6) in the control group (hazard ratio [HR] 0·69 [80% CI 0·56-0·85]; p=0·012; adjusted HR 0·70 [80% CI 0·57-0·87]; log-rank test p=0·018). The most frequent all-cause grade 3-4 adverse events were neutropenia (59 [42%] of 142 patients in the atezolizumab group vs 26 [36%] of 72 patients in the control group), diarrhoea (21 [15%] vs nine [13%]), and febrile neutropenia (14 [10%] vs seven [10%]). Serious adverse events were reported in 39 (27%) patients in the atezolizumab group and in 19 (26%) patients in the control group. Two (1%) treatment-related deaths (due to acute myocardial infarction and bronchopulmonary haemorrhage) were reported in the atezolizumab group; none were reported in the control group., Interpretation: The addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab is safe and improved progression-free survival in patients with previously untreated metastatic colorectal cancer., Funding: GONO Foundation, ARCO Foundation, F Hoffmann-La Roche, and Roche., Competing Interests: Declaration of interests DR received honoraria from Merck Sharp & Dohme (MSD). FP received honoraria from Amgen, Merck Serono, Lilly, Sanofi, Servier, Bayer, MSD, and AstraZeneca, and research grants from Bristol Myers Squibb (BMS) and AstraZeneca. AC, IB, AK, TS, JF, AP, and CM are Veracyte employees. LS received speaker and consultancy fees from MSD, AstraZeneca, Servier, Bayer, Merck, Amgen, and Pierre Fabre. SL has a consulting or an advisory role for Amgen, Merck Serono, Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, BMS, Servier, and MSD; has received research funding from Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and BMS; and has received speakers' fees from Roche, Lilly, BMS, Servier, Merck Serono, Pierre-Fabre, GlaxoSmithKline, and Amgen. FMo has received honoraria from Lilly and Servier. GT has a consultancy or an advisory role with BMS, AstraZeneca, MSD, Merck, and Servier. FG has received honoraria for speaker or advisory roles from Servier, Eli Lilly, Iqvia, Merck Serono, Amgen, and BMS. EM has received honoraria or consultation fees for speaker, consultancy, or advisory roles from Amgen, Bayer, Eisai, Merck Serono, Pierre Fabre, Roche, Servier, and Incyte. JG has patents associated with the immune prognostic and predictive biomarkers, and is co-founder of HalioDx, a Veracyte company. CC has received personal fees from Roche, Amgen, Bayer, Servier, Merck, MSD, Pierre Fabre, Nordic Pharma, and Organon; has received research funding from Merck Serono, Servier, Bayer, and Amgen; and has a consulting or an advisory role with Bayer, Amgen, Servier, and Pierre Fabre. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: The value of molecular markers in refining preoperative risk assessment of indeterminate thyroid nodules is being widely investigated. MicroRNAs (miRNA) are emerging as promising biomarkers for diagnostic and prognostic purposes. The aim of this study is to identify miRNAs specifically deregulated in mutation-negative indeterminate thyroid nodules., Methods: Ninety-eight nodules preoperatively diagnosed as TIR 3A or TIR 3B with available histological diagnosis of follicular adenoma (FA), noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP), and follicular variant papillary thyroid carcinoma (FV-PTC) have been retrospectively selected. Mutations in BRAF and RAS genes have been tested in all samples by real-time PCR; miRNAs were purified from cytology slides of 60 samples; expression analysis of 798 miRNAs was measured by the nCounter system., Results: Point mutations in BRAF and RAS genes were detected in 32 out of 98 nodules (32.7%), the majority of which in FV-PTCs. Differential expression of miRNA in wild-type nodules highlighted that two miRNAs, namely miR-7-5p and miR-548ar-5p, were downregulated in FV-PTCs compared to FAs. The combined expression of these miRNAs, tested by ROC analysis, showed an area under the curve of 0.79. Sensitivity and negative predictive value were high both in wild-type (93% and 92%, respectively) and in mutated nodules (94% and 85%, respectively)., Conclusion: The analysis of miR-7-5p and miR-548ar-5p expression in indeterminate thyroid nodules demonstrated a promising value in ruling out malignancy., (© 2022. The Author(s).)

In molecular pathology, predictive biomarkers identify which patients are likely to respond to targeted drugs. These therapeutic agents block specific molecules directly involved in cancer growth, dedifferentiation and progression. Until few years ago, the only targeted drugs available for advanced thyroid cancer included multi-tyrosine kinase inhibitors, mainly targeting the MAPK pathway and the angiogenic signaling. The administration of these drugs does not necessarily require a molecular characterization of tumors to assess the presence of predictive alterations. However, the availability of new selective targeted drugs for thyroid cancer patients is changing the diagnostic strategies for the molecular characterization of these tumors. The search for targetable alterations can be performed directly on tumor tissue by using a variety of methodologies, depending also on the number and type of alterations to test (i.e. single nucleotide variation or gene rearrangement). Herein, a comprehensive review of the currently available targeted treatments for thyroid cancer, related predictive markers and testing methodologies is provided., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Macerola, Poma, Vignali, Proietti, Ugolini, Torregrossa, Basolo, Elisei, Santini and Basolo.)

Metastatic colorectal cancer (mCRC) patients have poor chances of long term survival, being < 15% of them still alive after 5 years from diagnosis. Nonetheless, patients with colorectal liver metastases (CRLM) may be eligible for metastases resection thus being able to achieve long-term disease remission and survival. The likelihood for patients with CRLM of being or becoming eligible for liver metastasectomy is increasing, thanks to the evolution of surgical techniques, the availability of active systemic treatments and the widespread diffusion of experienced multidisciplinary boards to manage these patients. However, disease relapse after liver surgery is common and occurs in two-thirds of resected patients. Therefore, adequate radiological staging and risk stratification is crucial for the optimal selection of patients candidate to surgery in order to maximize the benefit-risk ratio of liver metastasectomy and to individualize the treatment strategy. Based on the multidimensional assessment, three possible approaches are available: upfront liver surgery followed by adjuvant chemotherapy, perioperative chemotherapy preceding and following liver surgery, and an upfront systemic treatment including chemotherapy plus a targeted agent, both chosen according to patients' and tumours' characteristics, then followed by liver surgery if indicated. In this review, we describe the most important factors impacting the therapeutic choices in patients with resectable and potentially resectable CRLM, and we discuss the most promising factors that may reshape the future decision-making process of these patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Large thyroid masses, particularly if rapidly growing, are often characterized by compression and infiltration of the vital structures of the neck. Therefore, an early and precise diagnosis, not only of malignancy but also of histotype, is mandatory to set up the right therapy. The aim of this study was to evaluate the diagnostic performance of fine needle aspiration cytology (FNAC) and core needle biopsy (CNB) in this setting., Patients and Methods: We prospectively evaluated 95 patients with large and rapidly growing thyroid masses admitted to the University Hospital of Pisa between April 2014 and January 2020. All patients were submitted to FNAC and CNB in the same session. The ability of both procedures to diagnose the malignancy of the lesions, particularly the histotype, and to obtain sufficient material to perform molecular analysis was evaluated., Results: FNAC obtained adequate tumor sample to reach a diagnosis in 76 of 95 (80%) patients, while a higher percentage was obtained with CNB (92/95, 96.8%). FNAC was able to identify the malignancy of the lesion in 74 of 95 (77.9%) cases, but only in 16 of 74 (21.6%) cases was it able to define the histotype. CNB was able to define the malignancy of the lesion in all but three cases (92/95, 96.8%), and in all specimens, the histotype was identified. Moreover, in all cases, the material extracted from CNB was optimal to perform molecular analysis. No surgery-related complications were experienced with both procedures., Conclusions: CNB is a rapid and safe procedure with higher performance compared to FNAC in identifying the histotype of large and rapidly growing thyroid masses. Moreover, adequate material can be obtained to characterize the molecular profile for the treatment of potentially lethal cancers. In the era of precision medicine, CNB should be introduced in routine clinical practice as a key procedure for an early diagnosis and therapy of these diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Matrone, De Napoli, Torregrossa, Aghababyan, Papini, Ambrosini, Cervelli, Ugolini, Basolo, Molinaro, Elisei and Materazzi.)

Papillary thyroid carcinoma (PTC) with hobnail areas above 30% is classified as hobnail variant (HVPTC). Although it is widely accepted that HVPTC has a worse outcome than classical PTC, it is unclear whether PTC with hobnail features below 30% is as aggressive as HVPTC. We gathered the largest mono-institutional series of PTC with hobnail areas and HVPTC to evaluate differences in terms of pathological features of aggressiveness, molecular profile, and treatment outcome. A total of 99 PTC with hobnail features above 5% were retrospectively selected; 34 of them met the criteria for HVPTC (0.4% of all PTC diagnosed at our institution). All tumors showed high rates of extra-thyroidal extension (40.4%), lymph node metastasis (68.1% of patients with lymphadenectomy), and vascular emboli (49.5%), with no differences according to the 30% cutoff. On the other hand, distant metastases were present in HVPTC only (9.4%). Also, advanced age, advanced disease stage, and TERT promoter mutation were associated with HVPTC. More than half of the patients with follow-up had structural or biochemical persistence after 1 year from surgery. Structural persistence was significantly more common in patients with HVPTC (37.5% vs. 8.7%), while no differences were observed considering structural and biochemical persistence together. The presence of hobnail features identifies locally aggressive tumors, and, consequently, it should be always acknowledged in the pathological report. However, tumors with more than 30% hobnail areas frequently present TERT promoter mutations, advanced disease stage, and structural persistence after radioiodine ablation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Poma, Macerola, Proietti, Vignali, Sparavelli, Torregrossa, Matrone, Basolo, Elisei, Santini and Ugolini.)

Objectives: This study is aimed to report a case of SV-related gastritis and the results of a systematic literature review of SV infections., Methods: Following a case presentation, we systematically searched different databases (MEDLINE, PubMed, Scopus, Web of Science, EMBASE, google scholar) for the items "sarcina," "ventriculi," "clostridium" with AND/OR., Results: A total of 55 articles reporting 65 cases of Sarcina Ventriculi were found. Thus, 66 patients, including our case, were reviewed. The median age was 51 years (IQR: 0-87 years). Females accounted for 51% of cases. 68% of patients had one or more comorbidities. SV was isolated in the gastrointestinal tract (88%), respiratory (5%), urine (4%), and bloodstream (3%) systems. Upper endoscopy was performed in 52 patients (79%). Biopsies were obtained in all 52 cases and were normal in 23%. Surgery was warranted in 15 patients (23%), and specific antimicrobial therapy was delivered in 34 (52%) patients. Mortality was 14%. At follow-up, 88% of patients showed complete eradication of the SV infection., Conclusions: Upper gastrointestinal biopsy positive for SV should prompt an evaluation of the clinical conditions, considering the risk of gastric perforation is not negligible. Antibiotic therapy may eradicate the infection and prevent complications. Emergency surgery is required in case of source control., Competing Interests: Declaration of Competing Interest No conflict of interest to declare., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Thyroid dysfunctions have been reported after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. However, the biological mechanisms behind these conditions remain unexplored. Herein, we report on changes of the immune transcriptome in autoptic thyroid tissues of people who have died from coronavirus disease 2019 (COVID-19). Methods: Twenty-five autoptic thyroid specimens of subjects dying from COVID-19 were investigated. Eleven autoptic thyroid specimens of subjects dying from causes other than infectious conditions served as controls. RNA transcripts of 770 immune-related genes together with RNA genomes of multiple coronavirus types were measured by the nCounter system. Reverse transcription - polymerase chain reaction for two SARS-CoV-2 genes was used to assess virus positivity. Results were validated by immunohistochemistry. Results: The SARS-CoV-2 genome and antigens were detected in 9 of 25 (36%) thyroid specimens from the COVID-19 cohort. Virus-negative thyroid tissues from COVID-19 subject did not show changes of gene transcription nor significant numbers of infiltrating immune cells. Conversely, SARS-CoV-2-positive thyroid specimens showed marked upregulation of immune genes, especially those proper of the type I and type II interferon (IFN) pathways. In infected tissues, infiltrates of innate immune cells (macrophages and polymorphonuclear neutrophils) were prevalent. Conclusions: The thyroid gland can be directly infected by the SARS-CoV-2. Infection strongly activates IFN pathways. The direct viral insult combined with an intense immune response may trigger or worsen thyroid conditions in predisposed individuals.

Context: Tumor capsule integrity is becoming a relevant issue to predict the biological behavior of human tumors, including thyroid cancer., Objective: This work aims to verify whether a whole tumor capsule in the classical variant of papillary thyroid carcinoma (CVPTC) could have as a predictive role of a good outcome as for follicular variant (FVPTC)., Methods: FVPTC (n = 600) and CVPTC (n = 554) cases were analyzed. We distinguished between encapsulated-FVPTC (E-FVPTC) and encapsulated-CVPTC (E-CVPTC) and, thereafter, invasive (Ei-FVPTC and Ei-CVPTC) and noninvasive (En-FVPTC and En-CVPTC) tumors, according to the invasion or integrity of the tumor capsule, respectively. Cases without a tumor capsule were indicated as invasive-FVPTC (I-FVPTC) and invasive-CVPTC (I-CVPTC). The subgroup of each variant was evaluated for BRAF mutations., Results: E-FVPTC was more frequent than E-CVPTC (P < .001). No differences were found between En-FVPTC and En-CVPTC or between Ei-FVPTC and Ei-CVPTC. After 18 years of follow-up, a greater number of not-cured cases were observed in Ei-CVPTC with respect to Ei-FVPTC, but not in En-CVPTC to En-FVPTC. Multivariate clustering analysis showed that En-FVPTC, En-CVPTC, and Ei-FVPTC have similar features but different from I-FVPTC and I-CVPTC and, to a lesser extent, from Ei-CVPTC. A total of 177 of 614 (28.8%) cases were BRAFV600E mutated, and 10 of 614 (1.6%) carried BRAF-rare alterations. A significantly higher rate of En-CVPTC (22/49, 44.9%) than En-FVPTC (15/195, 7.7%) (P < .0001) were BRAFV600E mutated., Conclusion: En-CVPTC is less prevalent than En-FVPTC. However, it has good clinical/ pathological behavior comparable to En-FVPTC. This finding confirms the good prognostic role of a whole tumor capsule in CVPTC as well. New nomenclature for En-CVPTC, similar to that introduced for En-FVPTC (ie, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NIFTP) could be envisaged., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Recent diagnostic criteria updates of the tall cell variant of papillary thyroid carcinoma (TCPTC) by the World Health Organization (WHO) have determined the inclusion of tumors with 30% to 49% of tall cells. However, the impact of tall cell percentage on papillary thyroid carcinoma (PTC) patients' prognosis is still debated., Objective: We aimed to evaluate whether tall cell percentage affects patient outcome in the absence of aggressive features., Methods: Rates of aggressive features, recurrence-free survival (RFS), and distant RFS (5-year median follow-up) were compared among tumors with less than 30%, 30% to 49% and at least 50% tall cells. We also evaluated the impact of the new tall cell cutoff on patient management., Results: Overall, 3092 tumors (15.7% of all PTCs) were collected: A total of 792 PTCs had less than 30%, 503 had 30% to 49%, and 1797 had 50% or more tall cell areas. With the new WHO definition, the number of TCPTCs increased by 28%. There were no differences in recurrence rates according to tall cell percentage. The coexistence of BRAF and TERT promoter mutations predicted a worse RFS. Considering the new definition of TCPTC, the level of risk according to the American Thyroid Association increased from low to intermediate in 4.2% of cases. However, the recurrence rate within this subgroup was comparable to low risk., Conclusion: TCPTC and PTC with tall cell areas can be considered as a unique group with similar recurrence risk. However, whenever aggressive features are absent, tumors have a low risk of recurrence independently of tall cell percentage., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We performed a comprehensive genomic profiling of tumour samples from metastatic colorectal cancer (mCRC) patients enrolled in the TRIBE2 study to assess the concordance among different techniques to evaluate mismatch repair (MMR) and microsatellite instability (MSI) status, to characterize tumours according to the tumour mutational burden (TMB) and explore the clinical relevance of different TMB cutpoints, and to investigate the prevalence of alterations actionable with targeted approaches or immune checkpoint inhibitors., Material and Methods: Tumour samples of 296 (44%) of 679 enrolled patients underwent 592-gene DNA next-generation sequencing (NGS). MMR status was assessed by immunohistochemistry (MMR-IHC), and MSI status was assessed by NGS (MSI-NGS). TMB was defined as low, intermediate, or high if <7, 7-16, or ≥17 mutations/megabase (mut/Mb) were found. The performance of TMB to predict MSI status was tested by receiver operating characteristic (ROC) curve. Actionable alterations included BRAF V600E, KRAS G12C, POLE mutations, HER2 amplification and mutations, and MSI-H., Results: Of 216 paired cases, concordance between MMR-IHC and MSI-NGS was 98.6%. Among 11 TMB-high tumours, eight (73%) were MSI-H and three (27%) were microsatellite stable and harboured POLE or MSH6 mutations. High TMB had a trend for a better outcome than low/intermediate TMB (hazard ratio for overall survival 0.45, 95% confidence interval 0.28-1.33; P = 0.106). No interaction effect between TMB and treatment arm was observed. Seventeen mut/Mb was identified as the optimal threshold of TMB for predicting MSI status. Actionable alterations were found in 62 (21%) of 296 patients., Conclusions: Genomic profiling provides an overview of the genomic landscape of mCRC in a single analysis, including actionable targets and markers of immune sensitivity., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: G.T. declares an advisory role with Lilly, Novartis, and Amgen. A.F. reports personal fees from Roche, Amgen, Merck Serono, Celgene, Bayer, and Sanofi; and research funding from Roche, Amgen, and Merck Serono. C.Cr. reports personal fees from Roche, Amgen, Bayer, and Servier; research funding from Merck Serono; and a consulting or advisory role with Roche, Bayer, Amgen. All other authors report no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Perivascular epithelioid cell tumors (PEComa)s are mesenchymal neoplasms located at various anatomic sites, which usually express both melanocytic and myogenic markers., Case Report: A 60-year-old woman underwent laparotomy for a huge, heterogeneous, right ovarian mass. The histological examination of the surgical specimen revealed a neoplasm consisting of both cells with clear or eosinophilic cytoplasm and spindle cells in a myxoid stroma. Immunostaining was positive for human melanoma black-45, h-caldesmon, desmin, actin, and transcription factor 3. Cell atypias were moderate, mitoses were 4/10 high power fields (HPF) and margins were focally infiltrative. These findings pointed to a diagnosis of ovarian PEComa. Twenty-five months later, two subcutaneous lesions were surgically removed on the left trapezius muscle and the median subumbilical area, respectively. The former was a desmoid fibromatosis, whereas the latter was a recurrence of PEComa with greater nuclear pleomorphism and higher number of mitoses (26/50 HPF) compared to the primary tumor. The patient was free of disease 11 months later., Conclusion: A long-term follow-up of gynecological PEComas is strongly recommended., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Recent data from the TRIBE2 study have failed to suggest a higher magnitude of benefit from upfront FOLFOXIRI/bevacizumab in patients with BRAF-mutant metastatic colorectal cancer (mCRC) as previously reported in the TRIBE study., Patients and Methods: Clinical characteristics and gene expression signatures of patients with BRAF-mutant mCRC enrolled in the TRIBE2 study were evaluated with the aim of understanding that patients may derive benefit from the intensification of the upfront chemotherapy., Results: Of 46 BRAF-mutant tumour samples analysed, 24 (52%) and 22 (48%) were classified as BM1 and BM2, respectively, and 27 (59%) and 19 (41%) were assigned to ligand-independent (LI) and ligand-dependent (LD) Wnt pathway subgroups, respectively. No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. No interaction was evident between BM1/BM2 or LI/LD signatures and the benefit provided by FOLFOXIRI/bevacizumab. Significant interaction effect was evident in terms of progression-free survival between treatment arm and primary tumour sidedness (P = 0.05) and Eastern Cooperative Oncology Group performance status (ECOG-PS; P < 0.001)., Conclusions: Gene expression analysis failed to identify patients with BRAF-mutant mCRC candidate to upfront FOLFOXIRI/bevacizumab. ECOG-PS >0 and left-sidedness seem associated with no benefit from the intensified treatment., Competing Interests: Conflicts of interest statement G.T. has a consulting or advisory role at Novartis, Amgen, and Lilly. A.F. received honoraria from Amgen, Lilly, Merck, Roche, and Servier; has consulting or advisory role at Amgen, Bayer, Bristol-Myers Squibb, Lilly, Merck, Roche, and Servier; received research funding from Amgen (Inst), Bayer (Inst), Merck (Inst), MSD (Inst), Roche (Inst), Sanofi (Inst), and Servier (Inst); received travel and accommodation expenses from Amgen, Bayer, Merck, Roche, and Servier. C.C. received honoraria from Amgen, Bayer, Merck, Roche, and Servier; has consulting or advisory role at Amgen, Bayer, MSD, and Roche; was a Speakers Bureau member at Servier; received research funding from Bayer, Merck, and Servier; received travel and accommodation expenses from Roche and Servier. All other authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Prophylactic central compartment lymph node dissection (pCCND) results in a higher percentage of surgical-related complications. To date, no evidence of the impact of pCCND on the clinical outcome of papillary thyroid carcinoma (PTC) patients with synchronous ipsilateral cervical lymph node metastases has been reported., Methods: We evaluated all consecutive patients affected by PTC and synchronous ipsilateral cervical, but without evidence of central compartment, lymph node metastases. We selected 54 consecutive patients (group A) treated by total thyroidectomy, ipsilateral cervical lymph node dissection, and pCCND and 115 patients (group B) matched for sex, age at diagnosis, number and dimension of the metastatic lateral cervical lymph nodes, without pCCND. Clinical outcome after a median of 5 years and surgical-related complications were assessed., Results: The two groups were completely similar in terms of clinical features. Clinical outcomes showed a higher percentage of biochemical and indeterminate but not structural response in group B. Group B required significantly more radioiodine treatments, but no difference was shown in the need to repeat surgery for recurrences. Conversely, the prevalence of permanent hypoparathyroidism was significantly higher in group A (14.8%) than in group B (4.3%)., Conclusion: In PTC patients with synchronous ipsilateral cervical lymph node metastases, in absence of clinically evident lymph node metastases of the central compartment, performing pCCND does not improve the 5-year outcome in terms of structural disease, despite a greater number of 131 I treatments. However, pCCND is severely affected by a higher percentage of permanent hypoparathyroidism, even in the hands of expert surgeons., Abbreviations: IQR = interquartile range; pCCND = prophylactic central compartment lymph node dissection; PTC = papillary thyroid carcinoma; Tg = thyroglobulin; US = ultrasound., (© 2020 American Association of Clinical Endocrinologists. Published by Elsevier, Inc. All rights reserved.)

Sporadic Medullary Thyroid Carcinoma (sMTC) is a rare but aggressive thyroid tumor. RET and RAS genes are present in about 50%-80% of cases, but most of the remaining cases are still orphan of a genetic driver. We studied the largest series of sMTC by deep sequencing to define the mutational landscape. With this methodology we greatly reduced the number of RET- or RAS-negative cases and we confirmed the central role of RET and RAS mutations. Moreover, we highlighted the bad prognostic role of RET mutations in sMTC and consolidated the favorable prognostic role of RAS mutations. For the first time, we showed that the variant allele frequency represents an additional prognostic marker inside the group of RET-mutated sMTC., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pourposes: We investigated the expression of RET9 and RET51 isoforms in medullary (MTC), papillary (PTC) thyroid carcinoma, normal thyroid tissues, and pheochromocytoma (PHEO) to verify if these isoforms are present also in follicular thyroid cell-derived tissues, and if there is a differential expression of RET9 and RET51 in MTC., Methods: Nineteen patients with MTC, 18 patients with PTC, 18 samples of contralateral normal thyroid tissues, and 5 cases of PHEO were included in this study. RET isoform expression was studied by real-time RT-PCR., Results: All MTCs and PHEOs were positive for RET9 and RET51. Fourteen/eighteen (77.7%) PTC cases were positive for RET9 and/or RET51, and four were positive for only one of the genes. In normal thyroid tissues, 3/18 (16.7%) cases were negative for both isoforms, 4/18 (22.2%) were positive for both, and 11/18 (61.1%) were positive for only one. RET isoforms were expressed at different levels in MTC, PHEO, PTC, and normal thyroid tissues: RET9 expression was higher in PHEO than in MTC, PTC, and normal thyroid tissues. RET9 expression was also higher in MTC than in PTC and normal thyroid tissues. No difference was observed between PTC and normal thyroid tissues. A similar pattern of expression was observed for RET51. In addition, RET51 was significantly more expressed than RET9 in MTC, while RET9 was the predominant isoform in PHEO., Conclusions: Our study documented the expression of the RET9 and RET51 isoforms in normal thyroid and PTC tissues. RET9 and RET51 isoforms were also present in MTC and PHEO. RET51 expression was higher than RET9 expression in MTC, while there was no difference in the expression of these two isoforms in PTC and normal thyroid tissues. RET9 was more highly expressed than RET51 in PHEOs.

Background: HER2 is the only validated predictive biomarker in gastro-oesophageal carcinoma (GOC). However, several factors, such as heterogeneity in protein expression, shortage of evaluable tumour tissue and need for quick target assessment, underline the usefulness of a pre-screening tool in order to anticipate HER2 status., Methods: Data from 723 consecutive GOC analysed for HER2 at four Italian Institutions were collected. HER2 positivity was defined as 3+ by immunohistochemistry (IHC) or 2+ with gene amplification by in situ hybridisation (ISH). A multivariate logistic regression model was built using data from 413 cases, whereas 310 patients served as validation cohort. C-index, visual inspection of the calibration plot, Brier score and Spiegelhalter z-test were used to assess the performance of the nomogram., Results: HER2 positive rate was 17.4%. Four variables were retained after adjustment in the final model: grading, Lauren's histotype, pathologic material analysed (surgical specimen/biopsy) and site of tissue collection (primary tumour/metastases). Visual inspection of the calibration plot revealed a very good overlap between predicted and observed probabilities, with a Brier score of 0.101 and a non-significant Spiegelhalter z-test (P = 0.319). C-index resulted in 0.827 (95%CI 0.741-0.913)., Conclusion: A simple nomogram based on always-available pathologic information accurately predicts the probability of HER2 positivity in GOC.

Context: Yes-associated protein-1 (YAP-1) is a player of the Hippo pathway and is involved in regulating cell proliferation. YAP-1 is overexpressed in papillary and anaplastic thyroid cancers. However, a correlation between YAP-1 expression and outcome in thyroid carcinoma has not been conclusively demonstrated., Objective: This study was designed to clarify whether YAP-1 may be considered a marker of worse prognosis and outcome in thyroid cancer., Design: A large series of cases of thyroid cancer with a long follow-up were investigated for YAP-1 expression., Setting: The study was carried out in the Pathology section of a referral Italian center for Endocrine Surgery and Endocrinology., Patients or Other Participants: The study included a consecutive series of 105 patients who underwent thyroidectomy from 1985 to 1992. The mean follow-up was 15 years. For all patients, clinicopathologic features were considered. All patients completed the study.The study also included a consecutive series of 52 patients who underwent thyroidectomy from 2012 to 2013 in order to analyze more deeply the correlation of YAP-1expression with BRAF mutation., Intervention: The 105 thyroid tumors were immunohistochemically investigated for YAP-1 expression., Outcome Measures: We expected a correlation between YAP-1 expression and worse prognosis., Results: Among 105 tumors, 77 scored positive for YAP-1 expression, of which 68 papillary thyroid carcinomas and 9 anaplastic thyroid carcinomas were YAP-1 positive. The correlation of YAP-1 expression with clinicopathologic characteristics was significant for the absence of a tumoral capsule, gender, and extrathyroid invasion.Interestingly, significant correlations were found between YAP-1 and both persistence of disease and death from carcinoma., Conclusions: The data show an association of YAP-1 expression with worse clinicopathologic features of thyroid tumors that seem to have a specific impact on outcome.

The encapsulated and noninvasive follicular variant of papillary thyroid carcinoma has been recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). These tumors demonstrate indolent behavior. This change in nomenclature will have great clinical impact by avoiding overtreatment of patients with NIFTP lesions who in the past were diagnosed with thyroid carcinoma and typically received completion thyroidectomy followed by radioactive iodine ablation. The pathologic diagnosis of NIFTP requires surgical removal of the thyroid lesion or the lobe harboring it, and thorough sampling of the complete interface between the tumor capsule and the thyroid parenchyma, to exclude foci of invasion. From a cytologic point of view, the unequivocal differential diagnosis between NIFTP and infiltrative follicular variant of papillary thyroid carcinoma in fine-needle aspiration is close to impossible based on cellular and architectural features. Therefore, use of adjunct molecular testing on fine-needle aspiration specimens may be essential for the preoperative diagnosis of low-risk tumors such as NIFTP for appropriate patient management. This review discusses and summarizes the existing known literature on molecular characteristics of NIFTP tumors, so far reported, including cases retrospectively classified or prospectively diagnosed as NIFTP. Brief reference is also made to new and promising approaches applicable to the diagnosis of this tumor.

Background: The diffuse sclerosing variant of papillary thyroid cancer (DSV-PTC) is a rare variant of papillary thyroid cancer (PTC) with different clinicopathological features compared with conventional PTC., Case: An advanced DSV-PTC was diagnosed in a 39-year-old man. The radioiodine posttherapeutic whole-body-scan showed only an uptake in the central neck, whereas the computerized tomography showed multiple latero-cervical and mediastinum lymph node metastases, a single and spiculated lung lesion and multiple bilateral cerebellum metastases. The patient died after 6 months from the initial diagnosis. The histological revision of the thyroid tumor confirmed the diagnosis of DSV-PTC, and its molecular analysis revealed a KIF5B/RET rearrangement that, until now, was described only in a minority of lung adenocarcinoma. Other 18 cases of DSV-PTC were then studied for the presence of KIF5B/RET rearrangement, but all of them were negative., Conclusions: This was a case of DSV-PTC positive for KIF5B/RET rearrangement, but considering that this alteration has been described only in lung adenocarcinoma and that the clinical course was more typical of lung carcinoma, we cannot completely rule out the possibility that this was a metastatic lesion from a lung tumor mimicking a DSV-PTC. As an alternative, we can also hypothesize that this was a case of fusion of two tumoral tissues deriving from a DSV-PTC and a metastasis of a KIF5B/RET positive lung adenocarcinoma. The question of whether the molecular findings, particularly when specifically reported only in some subtypes of human tumors, can overcome the morphological diagnosis is a matter of discussion., (Copyright © 2017 Endocrine Society)

BRAF mutations represent the most common genetic alteration in papillary thyroid carcinoma (PTC). The p.V600E mutation is specific for the classic and tall-cell variants of PTC and has been associated with a more aggressive biologic behavior. On the other hand, the p.K601E mutation is peculiar to the follicular variant of PTC, and seems to be a favorable prognostic indicator. A 12-year-old boy presented with a 10-mm left-sided thyroid nodule. Fine-needle aspiration cytology reported the lesion as suspicious for a follicular neoplasm (Bethesda category IV). The patient underwent lobectomy, and histopathology revealed a follicular adenoma with normal surrounding tissue. The cytological smear was found to be positive for BRAF p.K601E mutation, and this was later confirmed on the corresponding paraffin block. This case was independently revised by 4 expert pathologists, all of whom confirmed the benign nature of the thyroid lesion. This article describes the presence of a BRAF mutation in a benign thyroid lesion. To the authors' knowledge, this is the fourth case of follicular adenoma carrying BRAF K601E reported in literature to date. BRAF K601E mutation can occur in benign thyroid lesions. This finding, in the context of the current literature and the recently proposed reclassification of the noninvasive encapsulated follicular variant of papillary thyroid carcinoma into a benign lesion, confirms the importance of preoperative BRAF p.K601E testing in offering patients a tailored treatment plan and avoiding overtreatment.

Glycans containing α-L-fucose participate in diverse interactions between cells and extracellular matrix. High glycan expression on cell surface is often associated with neoplastic progression. The lysosomal exoenzyme, α-L-fucosidase-1 (FUCA-1) removes fucose residues from glycans. The FUCA-1 gene is down-regulated in highly aggressive and metastatic human tumors. However, the role of FUCA-1 in tumor progression remains unclear. It is speculated that its inactivation perturbs glycosylation of proteins involved in cell adhesion and promotes cancer. FUCA-1 expression of various thyroid normal and cancer tissues assayed by immunohistochemical (IHC) staining was high in normal thyroids and papillary thyroid carcinomas (PTC), whereas it progressively decreased in poorly differentiated, metastatic and anaplastic thyroid carcinomas (ATC). FUCA-1 mRNA expression from tissue samples and cell lines and protein expression levels and enzyme activity in thyroid cancer cell lines paralleled those of IHC staining. Furthermore, ATC-derived 8505C cells adhesion to human E-selectin and HUVEC cells was inhibited by bovine α-L-fucosidase or Lewis antigens, thus pointing to an essential role of fucose residues in the adhesive phenotype of this cancer cell line. Finally, 8505C cells transfected with a FUCA-1 containing plasmid displayed a less invasive phenotype versus the parental 8505C. These results demonstrate that FUCA-1 is down-regulated in ATC compared to PTC and normal thyroid tissues and cell lines. As shown for other human cancers, the down-regulation of FUCA-1 correlates with increased aggressiveness of the cancer type. This is the first report indicating that the down-regulation of FUCA-1 is related to the increased aggressiveness of thyroid cancer.

Follicular variants of papillary thyroid carcinoma include encapsulated (with or without capsular/vascular invasion) and infiltrative forms, which have different clinical behaviors. The encapsulated forms that lack capsular invasion have an indolent clinical behavior that is similar to benign lesions; therefore, they were recently reclassified as 'noninvasive follicular thyroid neoplasms with papillary-like nuclear features' (NIFTPs). Because NIFTPs have nuclear features of papillary carcinomas, distinguishing between NIFTPs and infiltrative follicular variant of papillary thyroid carcinoma is almost impossible with cytological examination. The aim of this study is to determine whether miRNA expression profiles may help distinguish between NIFTPs versus follicular adenomas and infiltrative follicular variant of papillary thyroid carcinomas. The expression profiling of 798 miRNAs was tested in 54 thyroid tumors, including 18 follicular adenomas, 19 NIFTPs and 17 infiltrative follicular variant of papillary thyroid carcinomas, using nCounter Nanostring. We found that miR-146-5p, miR-221-5p, miR-222-3p, miR-30e-3p, and miR-152-3p could discriminate between benign and malignant lesions with a very high level of significance (P-value<0.001). High expression levels of miR-146-5p, miR-199a-5p, miR-199b-5p, miR-1285-5p, miR-1915-3p, and miR-4516, and low miR-148b-3p expression were associated with infiltrative growth of follicular variant of papillary thyroid carcinomas. Interestingly, miR-152-3p, miR-185-5p, and miR-574-3p were significantly downregulated in NIFTPs compared with follicular adenomas, whereas miR-10a-5p and miR-320e can discriminate between NIFTPs and infiltrative forms of follicular variant of papillary thyroid carcinomas. In conclusion, a panel of these markers could have high diagnostic potential as well as could be applied to presurgical fine-needle aspiration, especially for lesions classified as indeterminate thyroid nodules.

Fine-needle aspiration (FNA) is routinely used in the preoperative evaluation of thyroid nodules. However, 15% to 30% of aspirations yield indeterminate cytologic findings. Because the assessment of BRAF mutations seems to improve the diagnostic accuracy, this study evaluated BRAF mutations with Sanger sequencing and real-time methods in 650 consecutive thyroid aspirates. In addition, the expression of a large number of genes involved in basement membrane remodeling, extracellular matrix proteolysis, and cell adhesion was studied in both benign and malignant nodules to identify new diagnostic tools. In this prospective series, despite the use of a very sensitive BRAF mutational testing method, the frequency of a BRAF alteration being identified in indeterminate FNA samples was 3 of 68. Expression analysis revealed several genes that were differentially expressed between benign and malignant nodules (transforming growth factor, cadherin 1, collagen α1, catenin α1, integrin α3, and fibronectin 1 [FN1]), between follicular adenomas and follicular variant of papillary thyroid carcinoma (FN1, laminin γ1, integrin β2, connective tissue growth factor, catenin δ1, and integrin αV), and between BRAF-wild-type and BRAF-mutated papillary thyroid carcinomas (TIMP metallopeptidase inhibitor 1; catenin α1; secreted phosphoprotein 1; FN1; ADAM metallopeptidase with thrombospondin type 1 motif, 1; and selectin L). These data were partially confirmed with real-time polymerase chain reaction analysis and immunohistochemistry. When the cost/benefit ratio of the procedures was taken into account, BRAF mutational testing failed to increase diagnostic accuracy in cytologically indeterminate nodules. However, the additional analysis of the expression of specific molecular markers could have possible utility as a diagnostic tool, although further evidence based on a large series of samples is needed before definitive conclusions can be drawn. Cancer Cytopathol 2016;124:340-9. © 2015 American Cancer Society., (© 2015 American Cancer Society.)

Purpose: The purpose of this study was to detect the role of serum tumor markers in the differential diagnosis and in the choice of the surgical treatment of ovarian lesions in pediatric age., Methods: We retrospectively reviewed medical charts of all pediatric girls operated in two pediatric centers during a 10-year period. The following features were analyzed: age at the moment of presentation, symptoms, diagnostic studies, surgical approach, pathological findings, and, in particular, serum tumor markers. Also, a literature review and statistical analysis (χ(2) test) concerning the increase of different tumor markers in benign and malignant ovarian lesions were related to the study., Results: A total of 120 children with 127 ovarian masses (7 with bilateral pathologies) were reviewed. Pathology showed 61 nonneoplastic lesions (48%), 54 benign tumors (42.5%), 5 malignant tumors (4%), and 7 torsed normal ovaries (5.5%). The evaluation of serum tumor markers was performed in 106 cases and was positive in 16 (15.1%): in all of the 5 cases (100%) of malignant neoplastic lesions and in 11 (20.4%) benign neoplastic ones. The literature review confirmed these data, and statistical analysis highlighted them as significant values., Conclusions: The role of tumor markers is still controversial. This is the reason why, before considering a radical treatment, we suggest caution to optimize future fertility.

Objective: To analyze aspects of a series of papillary thyroid carcinomas and evaluate the prognostic features specific to different age classes., Study Design: Retrospective study., Subjects and Methods: From 2000 to 2005, 2709 patients underwent a total thyroidectomy for papillary thyroid carcinoma in our department. Patients were divided into three groups: <18 years (G1), 19 to 45 years (G2), and >46 years (G3). Histologic and clinical features were statistically evaluated., Results: Tumor size was larger in G1 when compared with both G2 and G3 (P < 0.0001). Infiltration of the thyroid capsule and node metastases were higher in G1 than both G2 and G3 (P < 0.0001). The Tall-cell variant was more represented in G2 and G3., Conclusion: In the pediatric population, papillary carcinoma is a more aggressive disease. Because pediatric cancers have a better prognosis than their adult counterparts, this does not influence patient outcome. Age can then be considered the most important factor in determining prognosis.

Total thyroidectomy and central neck dissection are the procedures of choice in patients affected with medullary thyroid cancer. It is known that a medullary thyroid cancer with node metastases can be rarely cured, and therefore the utility of a modified radical neck dissection in the absence of suspicious node metastases still needs further evidence. The study aims to verify whether other epidemiological and pathological parameters could affect the prognosis of medullary thyroid cancer patients. We prospectively studied 70 medullary thyroid cancer patients consecutively operated on (from 2000 to 2004) at the same institution and analysed by the same pathologists. All patients underwent total thyroidectomy and central lymphadenectomy. In 27 cases, the ipsilateral (n=19) or bilateral (n=8) modified radical neck dissection was performed in the presence of suspicious lateral neck node metastases. After surgical treatment, basal and stimulated serum calcitonins (Cts) were measured in all patients. Follow-up ranged between 1 and 4 years. Patients were considered 'cured' when stimulated Ct was undetectable. Age, sex, tumour size, tumour capsule, multicentricity, nodes in the central neck and mean number of positive nodes were analysed in 'cured' and 'not-cured' patients. The presence of node metastases in the central compartment was significantly correlated with the outcome of the patients, being present in 9 and 72% of cured and not-cured patients respectively (P<0.000001). Tumour size was also significantly correlated with the outcome of the disease (P<0.00006). The presence of the tumour capsule correlated with better prognosis (P=0.0005) and absence of node metastases (P=0.0080). By multivariate analysis, the presence of node metastasis remained the most significant variable affecting the outcome of the disease (P=0.000014). Our results show that the outcome of encapsulated cancer is significantly better regardless of tumour size and node metastases. Although the early diagnosis and the extensive surgical treatment may favour the good outcome of medullary thyroid cancer, they do not always guarantee the definitive cure of the disease, being the capsular infiltration an independent bad prognostic factor.