Multicancer screening test based on the detection of circulating non haematological proliferating atypical cells.

BACKGROUND: the problem in early diagnosis of sporadic cancer is understanding the individual's risk to develop disease. In response to this need, global scientific research is focusing on developing predictive models based on non-invasive screening tests. A tentative solution to the problem may be a cancer screening blood-based test able to discover those cell requirements triggering subclinical and clinical onset latency, at the stage when the cell disorder, i.e. atypical epithelial hyperplasia, is still in a subclinical stage of proliferative dysregulation. METHODS: a well-established procedure to identify proliferating circulating tumor cells was deployed to measure the cell proliferation of circulating non-haematological cells which may suggest tumor pathology. Moreover, the data collected were processed by a supervised machine learning model to make the prediction. RESULTS: the developed test combining circulating non-haematological cell proliferation data and artificial intelligence shows 98.8% of accuracy, 100% sensitivity, and 95% specificity. CONCLUSION: this proof of concept study demonstrates that integration of innovative non invasive methods and predictive-models can be decisive in assessing the health status of an individual, and achieve cutting-edge results in cancer prevention and management.

Programmed Cell Death Ligand 1 (PD-L1) Immunohistochemical Expression in Advanced Urothelial Bladder Carcinoma: An Updated Review with Clinical and Pathological Implications.

The management of advanced bladder carcinoma involves a multidisciplinary approach, but the prognosis remains poor for many patients. The immune system plays a crucial role in this disease, influencing both tumor development and response to treatment, and exploiting the immune system against the tumor can be a valuable strategy to destroy neoplastic cells. This is the biological principle underlying Bacillus Calmette-Guérin (BCG) use and, more recently, immune checkpoint inhibitors (ICIs), like PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) inhibitors. In fact, one of the best studied immune checkpoints is represented by the PD-1/PD-L1 axis, which is a well-known immune escape system adopted by neoplastic bladder cells. PD-L1 expression has been associated with a higher pathologic stage and has shown prognostic value in bladder carcinoma. Interestingly, high-grade bladder cancers tend to express higher levels of PD-1 and PD-L1, suggesting a potential role of such an axis in mediating disease progression. Immunotherapy with PD-1 and PD-L1 inhibitors has therefore emerged as a valuable treatment option and has shown efficacy in advanced bladder cancer patients, with high PD-L1 expression levels associated with better treatment responses. Our review aims to provide a comprehensive overview of the role of PD-L1 in advanced bladder cancer, focusing on its implications for treatment decisions and the prediction of treatment response. Overall, our work aims to contribute to the understanding of PD-L1 as a predictive biomarker and highlight its role in shaping therapeutic approaches for advanced bladder cancer.

Relevance of the College of American Pathologists guideline for validating whole slide imaging for diagnostic purposes to cytopathology.

Whole slide imaging (WSI) allows pathologists to view virtual versions of slides on computer monitors. With increasing adoption of digital pathology, laboratories have begun to validate their WSI systems for diagnostic purposes according to reference guidelines. Among these the College of American Pathologists (CAP) guideline includes three strong recommendations (SRs) and nine good practice statements (GPSs). To date, the application of WSI to cytopathology has been beyond the scope of the CAP guideline due to limited evidence. Herein we systematically reviewed the published literature on WSI validation studies in cytology. A systematic search was carried out in PubMed-MEDLINE and Embase databases up to November 2021 to identify all publications regarding validation of WSI in cytology. Each article was reviewed to determine if SRs and/or GPSs recommended by the CAP guideline were adequately satisfied. Of 3963 retrieved articles, 25 were included. Only 4/25 studies (16%) satisfied all three SRs, with only one publication (1/25, 4%) fulfilling all three SRs and nine GPSs. Lack of a suitable validation dataset was the main missing SR (16/25, 64%) and less than a third of the studies reported intra-observer variability data (7/25, 28%). Whilst the CAP guideline for WSI validation in clinical practice helped the widespread adoption of digital pathology, more evidence is required to routinely employ WSI for diagnostic purposes in cytopathology practice. More dedicated validation studies satisfying all SRs and/or GPSs recommended by the CAP are needed to help expedite the use of WSI for primary diagnosis in cytopathology.

Delphi expert consensus for whole slide imaging in thyroid cytopathology.

OBJECTIVE: Despite an increase in thyroid fine needle aspiration (FNA) and advances in whole slide imaging (WSI) adoption, digital pathology is still considered inadequate for primary diagnosis of these cases. Herein, we aim to validate the utility of WSI in thyroid FNAs employing the Delphi method strategy. METHODS: A panel of experts from seven reference cytology centres was recruited. The study consisted of two consecutive rounds: (1) an open-ended, free-response questionnaire generating a list of survey items; and (2) a consensus analysis of 80 selected shared WSIs from 80 cases by six investigators answering six morphological questions utilising a 1 to 5 Likert scale. RESULTS: High consensus was achieved for all parameters, with an overall average score of 4.27. The broad majority of items (84%) were ranked either 4 or 5 by each physician. Two badly scanned cases were responsible for more than half of the low-ranked (≤2) values (57%). Good to excellent (≥3) diagnostic confidence was reached in more than 95.2% of cases. For most cases (78%) WSI assessment was not limited by technical issues linked to the image acquisition process. CONCLUSION: This systematic Delphi study indicates broad consensus among participating physicians on the application of DP to thyroid cytopathology, supporting expert opinion that WSI is reliable and safe for primary diagnostic purposes.

Bladder Epicheck Test: A Novel Tool to Support Urothelial Carcinoma Diagnosis in Urine Samples.

Bladder cancer and upper urothelial tract carcinoma are common diseases with a high risk of recurrence, thus necessitating follow-up after initial treatment. The management of non-muscle invasive bladder carcinoma (NMIBC) after transurethral resection involves surveillance, intravesical therapy, and cytology with cystoscopy. Urinary cytology, cystoscopy, and radiological evaluation of the upper urinary tract are recommended during follow-up in the international urological guidelines. Cystoscopy is the standard examination for the first assessment and follow-up of NMIBC, and urine cytology is a widely used urinary test with high sensitivity for high-grade urothelial carcinoma (HGUC) and carcinoma in situ (CIS). In recent years, various urinary assays, including DNA methylation markers, have been used to detect bladder tumors. Among these, the Bladder EpiCheck test is one of the most widely used and is based on analysis of the methylation profile of urothelial cells to detect bladder neoplasms. This review assesses the importance of methylation analysis and the Bladder EpiCheck test as urinary biomarkers for diagnosing urothelial carcinomas in patients in follow-up for NMIBC, helping cytology and cystoscopy in doubtful cases. A combined approach of cytology and methylation analysis is suggested not only to diagnose HGUC, but also to predict clinical and histological recurrences.

BRAF-AXL-PD-L1 Signaling Axis as a Possible Biological Marker for RAI Treatment in the Thyroid Cancer ATA Intermediate Risk Category.

The use of radioiodine therapy (RIT) is debated in intermediate-risk differentiated thyroid cancer (DTC) patients. The understanding of the molecular mechanisms involved in the pathogenesis of DTC can be useful to refine patient selection for RIT. We analyzed the mutational status of BRAF, RAS, TERT, PIK3 and RET, and the expression of PD-L1 (as a CPS score), the NIS and AXL genes and the tumor-infiltrating lymphocytes (TIL, as the CD4/CD8 ratio), in the tumor tissue in a cohort of forty-six ATA intermediate-risk patients, homogeneously treated with surgery and RIT. We found a significant correlation between BRAF mutations and a less than excellent (LER, according to 2015 ATA classification) response to RIT treatment (p = 0.001), higher expression of the AXL gene (p = 0.007), lower expression of NIS (p = 0.045) and higher expression of PD-L1 (p = 0.004). Moreover, the LER patient group had a significantly higher level of AXL (p = 0.0003), a lower level of NIS (p = 0.0004) and a higher PD-L1 level (p = 0.0001) in comparison to patients having an excellent response to RIT. We also found a significant direct correlation between the AXL level and PD-L1 expression (p < 0.0001) and a significant inverse correlation between AXL and NIS expression and TILs (p = 0.0009 and p = 0.028, respectively). These data suggest that BRAF mutations and AXL expression are involved in LER among DTC patients and in the higher expression of PD-L1 and CD8, becoming new possible biomarkers to personalize RIT in the ATA intermediate-risk group, as well as the use of higher radioiodine activity or other possible therapies.

Evaluating programmed death-ligand 1 (PD-L1) in head and neck squamous cell carcinoma: concordance between the 22C3 PharmDx assay and the SP263 assay on whole sections from a multicentre study.

AIMS: The introduction of immunotherapy for patients with head and neck squamous cell carcinoma (HNSCC) raises the need for harmonisation between different types of antibody and immunohistochemistry platform for evaluating the expression of PD-L1 by use of the combined positive score (CPS) in this tumour. The aim of this study was to compare the expression of PD-L1 as determined with the CPS and two widely used assays (the 22C3 PharmDx assay and the SP263 assay) in a cohort of HNSCCs. METHODS AND RESULTS: We analysed 43 whole sections of HNSCC with two different anti-PD-L1 antibodies, 22C3 and SP263. The results, expressed as the CPS, were evaluated by 10 trained pathologists and statistical analyses were performed. We found a very similar results for PD-L1 expression between the 22C3 PharmDx assay and the SP263 assay in our cohort, and a strong and significant correlation between the two assays for all specimens (P < 0.0001). The interobserver reliability among pathologists for the continuous scores of CPS with the intraclass correlation coefficient and the correlation between the two assays were both good. Moreover, the rate of agreement between assays was high at all cut-offs and was best for the most relevant cut-off of CPS ≥ 1, and the kappa values were always in the range of almost perfect. CONCLUSIONS: Two different assays (the 22C3 PharmDx assay and SP263 assay) for PD-L1 in HNSCC showed high agreement. These data suggest that these two assays are interchangeable in the selection of patients with HNSCC for immunotherapy.

DOG1 as an Immunohistochemical Marker of Acinic Cell Carcinoma: A Systematic Review and Meta-Analysis.

DOG1 is a transmembrane protein originally discovered on gastrointestinal stromal tumors and works as a calcium-activated chloride channel protein. There are a limited number of articles on the potential utility of this antibody in the diagnosis of salivary gland tumors in routine practice. In this study, we aimed to investigate the role of DOG1 as an immunohistochemical marker in patients with salivary acinic cell carcinoma (ACC) through meta-analysis. A literature search was performed of the PubMed, Scopus, and Web of Science databases for English-language studies published from January 2010 to September 2021. The literature search revealed 148 articles, of which 20 were included in the study. The overall rate of DOG1 expression in salivary acinic cell carcinoma was 55% (95% CI = 0.43-0.58). Although ACC is a challenging diagnosis, paying careful attention to the cytomorphological features in conjunction with DOG1 immunostaining can help to reach an accurate diagnosis.

Relevance of rosette patterns in variants of papillary thyroid carcinoma.

INTRODUCTION: The detection of rosette-like clusters (RLC) of follicular cells in thyroid carcinoma has been reported mostly in the columnar cell variant of papillary thyroid carcinoma (PTC). Despite the fact that diagnosing variants of PTC is no longer encouraged by The Bethesda System for Reporting Thyroid Cytopathology, the identification of cytomorphological features such as RLC linked with these tumours might help reduce possible misinterpretation in thyroid fine needle aspiration (FNA) cytology. We accordingly investigated the potential correlation of architectural patterns including RLC with PTC variants. METHODS: We analysed 225 thyroid FNA cytology cases diagnosed as suspicious for malignancy (SFM) and positive for malignancy (M) over a 1-year time where all samples had corresponding histology. We also included 150 benign lesions from the same period. The presence of RLC vs similar appearing solid clusters, papillary structures and microfollicles were evaluated. We also performed immunocytochemistry and molecular testing for BRAFV600E. RESULTS: We included 100 (44.4%) SFM favouring PTC and 125 (55.6%) M cases with cyto-histological correlation. On histology, all SFM and M cases showed malignancy including 140 (62.2%) classic PTC and 85 (37.8%) PTC variants. The cytomorphological patterns in all FNA samples included solid (74%), papillary (89%), microfollicular (70%), and pseudo-RLC morphology (25.7%). We identified only pseudo-RLC in 33 FNA specimens from PTC variant cases that included tall cell variant (42.4%), hobnail variant (21.2%) and miscellaneous variants (36.3%) of PTC. No definitive RLC were detected in our series. Immunocytochemistry and BRAFV600E were not specifically linked with an RLC pattern. CONCLUSIONS: These findings demonstrate that in our dataset the architectural pattern of RLC was not recognised within PTC variants. However, we did identify a pseudo-RLC pattern that was observed in association with tall cell variant and hobnail variant cases of PTC.

Biosafety procedures for handling intraoperative surgical samples during COVID-19 pandemic: an Italian pathology laboratory experience.

Up to now, Italy is one of the European centers with the most active Coronavirus cases with 233,836 positive cases and 33,601 total deaths as of June 3rd. During this pandemic and dramatic emergency, Italian hospitals had also to face neoplastic pathologies, that still afflict the Italian population, requiring urgent surgical and oncological treatment. In our Cancer Center Hospital, the high volume of surgical procedures have demanded an equally high volume of intraoperative pathological examinations, but also posed an additional major challenge for the safety of the staff involved. The current commentary reports our experience in the past two months (since March 9th) for a total of 1271 frozen exams from 893 suspect COVID-19 patients (31 confirmed).

Comparison between cytospin and liquid-based cytology in cerebrospinal fluid diagnosis of neoplastic diseases: A single institution experience.

OBJECTIVE: The current tools available for detecting malignant neoplasms in the cerebrospinal fluid (CSF) are neurological examination, followed by neuroimaging, cytology and molecular techniques. To highlight the role of cytology the diagnosis of metastatic tumours in CSF samples, we present our experience using cytospin and ThinPrep liquid-based cytology. METHODS: A retrospective analysis was conducted using the pathological records of 8181 cytological specimens of CSF, which were diagnosed over a 17-year period. Between 2000 and 2014, a total of 6994 CSF samples were processed using cytospin method and 1187 specimens were examined using ThinPrep method in the period between 2015 and 2017. RESULTS: The most frequent metastatic neoplasm of the first period was non-Hodgkin lymphoma; in the second period the commonest malignancy found was brain tumour (glioblastoma and medulloblastoma). The samples processed by cytospin revealed cytolysis and haemorrhage, while the cases processed by ThinPrep had a clear background. Ten false-positive cases belonging to the suspicious category were processed by cytospin, while there was only one false positive case in the group processed by ThinPrep. The positive predictive value was 95% in cytospin and 100% in Thin Prep with comparable sensitivity, specificity, diagnostic accuracy and negative predictive values. CONCLUSIONS: CSF cytology is a reliable technique for identifying malignancy in CSF. ThinPrep technology can be applied with good results in terms of clear background, cell enrichment, better nuclear details and high cellularity per slide.

The immunocytochemical expression of VE-1 (BRAF V600E-related) antibody identifies the aggressive variants of papillary thyroid carcinoma on liquid-based cytology.

BACKGROUND: The recently introduced monoclonal V600E antibody (clone VE1) is likely to be an alternative strategy for detecting this mutation in thyroid lesions. Although VE1 immunostaining and molecular methods used to assess papillary thyroid carcinoma in surgical specimens are in good agreement, evaluation of VE1 in cytology and cell block samples is rarely performed, and its diagnostic value in cytology has not been well established. In this study, we sought to determine if VE1 is suitable for fine needle aspiration (FNA) and cell block methods. METHODS: A total of 86 patients who had BRAF V600E mutations were investigated with molecular and immunocytochemical (ICC) analysis in 45 FNA and 41 cell blocks. In total, 83 (96.5%) patients underwent surgical treatment. Assessment of BRAF V600E mutation status was performed in 72 (83.7%) cases. RESULTS: Among the 72 cases analysed, 54 cases agreed (ICC+/BRAF+ or ICC-/BRAF-), seven cases were false positive (ICC+/BRAF-) and 11 cases were false negative (ICC-/BRAF+). False negative cases were not detected in the cell block method. The statistical analysis showed that sensitivity and specificity of ICC for detecting the BRAF V600E mutation were 61% and 77% in FNA samples and 100% and 73% in cell block. CONCLUSION: The use of antibody VE-1 is a reliable method and a negative result of VE1 immunostaining might help to save time and money, restricting the molecular test to antibody-positive cases only. The identification of the aggressive variants of papillary carcinoma might be enabled by the expression of the antibody in neoplastic cells with tall cell features.

Cyto-histology in NET: what is necessary today and what is the future?

The carcinoid as originally described is part of the relatively large family of neuroendocrine neoplasia found in almost every organ. Historical reasons back their current definitions. Neuroendocrine cancer is most frequently observed in the lung and the digestive tract. In the lung is defined as carcinoid (typical and atypical) for well differentiated, low to intermediate grade, and small cell and large cell neuroendocrine carcinoma for poorly differentiated, high grade. In the digestive system are respectively defined as neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC) of small and large cell types. Grading and staging are developed for their clinical classification by the World Health Organization (WHO) and the American Joint Committee on Cancer (AJCC). In both anatomical sites the morphological features are overlapping, with bland histology for carcinoid and NET, and aggressive features with extensive necrosis, severe atypia and abundant, atypical mitoses for high grade cancer types. Such features are also essential diagnostic clues in cytological preparations. The confirmation of the neuroendocrine signature by immunohistochemistry is mandatory for the diagnosis; a minimum panel comprising chromogranin A and synaptophysin is recommended in the digestive system. In addition, the application of grading requires the mitotic count and or spotty necrosis assessment for lung, or the mitotic count and the Ki67 assessment in the digestive system.

Ipsilateral Central Neck Dissection Plus Frozen Section Examination Versus Prophylactic Bilateral Central Neck Dissection in cN0 Papillary Thyroid Carcinoma.

BACKGROUND: Ipsilateral central compartment node dissection (IpsiCCD) can reduce the morbidity of prophylactic bilateral central compartment node dissection (BilCCD) in papillary thyroid carcinoma (PTC) but it carries the risk of contralateral metastases being overlooked. Frozen section examination (FSE) of removed ipsilateral nodes has been proposed to intraoperatively assess nodal status. We compared IpsiCCD plus FSE and BilCCD in clinically unifocal and node negative PTC. METHODS: One hundred patients were prospectively assigned to undergo total thyroidectomy (TT) plus BilCCD or TT plus IpsiCCD. In the IpsiCCD group, removed lymph nodes were sent for FSE. If FSE was positive for metastases, a BilCCD was accomplished. RESULTS: The two groups included 50 patients each. Overall, occult lymph node metastases were found in 41 patients-20 in the IpsiCCD group and 21 in the BilCCD group. FSE correctly identified occult node metastases in 13 of 20 pN1a patients in the IpsiCCD group (overall accuracy 86 %). Seven node metastases were not detected at FSE-five were micrometastases (≤2 mm). Six of 13 patients in the IpsiCCD group who underwent BilCCD and 6 of 21 BilCCD pN1a patients had bilateral metastases. More patients in the BilCCD group showed transient hypocalcemia (27/50 vs. 18/50, respectively) [p = NS]. No patient experienced recurrent disease. CONCLUSIONS: FSE of ipsilateral nodes is accurate in determining nodal status, allowing the extension of the central neck clearance to be reliably modulated. Routine IpsiCCD plus FSE of the ipsilateral nodes could be a valid alternative to prophylactic BilCCD since it allows accurate staging and may reduce morbidity.

Performance of the forward-viewing linear echoendoscope for fine-needle aspiration of solid and cystic lesions throughout the gastrointestinal tract: a large single-center experience.

BACKGROUND: A newly developed forward-viewing linear echoendoscope (FV-EUS) has recently become available. To date, however, only scanty data on the performance of the FV-EUS scope for fine-needle aspiration (FNA) of lesions throughout the gastrointestinal (GI) tract are available. This study aimed to evaluate the technical performance of the FV-EUS scope for FNA of solid and cystic lesions located throughout the GI tract in a large cohort of patients referred to a tertiary care center. METHODS: All patients who underwent endoscopic ultrasound (EUS)-guided FNA using the FV-EUS scope between January 2007 and December 2008 were included in this retrospective study. The performance of the FV-EUS scope for FNA was evaluated. RESULTS: During the study period, 285 patients with solid or cystic lesions throughout the GI tract underwent the procedure with the FV-EUS scope. A total of 300 FNAs were attempted, 6 (2%) of which could not be performed. Of the 294 successful EUS-FNA procedures, 130 (44.2%) were performed using a 22-gauge needle, 89 (30.3%) using a 25-gauge needle, and 75 (25.5%) using a 19-gauge needle. In all 67 cases of pancreatic cyst or dilated pancreatic duct, a specimen for cystic fluid analysis or cytologic examination could be obtained. Among the remaining 217 patients with solid lesion, a definitive diagnosis could be established for 211 patients (97.2%). The FV-EUS scope had a sensitivity of 74.7% (95% confidence interval [CI] 68.1-80.6%), a specificity of 100% (95% CI 89.9-100%), a positive likelihood ratio of infinity, and a negative likelihood ratio of 0.251 (95% CI 0.196-0.323). CONCLUSIONS: The FV-EUS scope is highly effective for FNA of solid and cystic lesions throughout the GI tract. Prospective studies comparing the FV-EUS scope and a curved linear scope are needed.

The nightmare of indeterminate follicular proliferations: when liquid-based cytology and ancillary techniques are not a moon landing but a realistic plan.

OBJECTIVE: Thyroid nodules are a common finding in the general population, including both nonneoplastic and neoplastic entities. Fine-needle aspiration cytology (FNAC) is the first tool for evaluating thyroid nodules. In spite of its high diagnostic accuracy, 25% of nodules result in the category of follicular neoplasms (FN), with varying risk of malignancy and different management strategies. STUDY DESIGN: The use of ancillary techniques is reshaping the practice of FNAC. These tools can significantly empower the morphological diagnosis and prognosis of thyroid nodules, allowing a more accurate prediction of the nature of the lesion. Several studies have underlined the role of single or multiple testing for the category of FN as strong indicators of cancer. Every cytological preparation can be used for the application of ancillary techniques but the introduction of liquid-based cytology (LBC) might facilitate the application. RESULTS: Our experience involving an immunocytochemical panel made up of HBME-1 and galectin-3 pointed to an 81% overall diagnostic accuracy in discriminating between low and high risk of malignancy in FN. CONCLUSIONS: The application of these techniques on LBC represents an adjunct to the morphological evaluation of FN. They represent a critical and challenging, but also a feasible, tool in the preoperative diagnoses, allowing specific prognostic and predictive details regardless of the cytological preparation. © 2014 S. Karger AG, Basel.

Actual incidence and clinical behaviour of follicular thyroid carcinoma: an institutional experience.

Follicular thyroid carcinoma classically accounts for 10-32% of thyroid malignancies. We determined the incidence and the behaviour of follicular thyroid carcinoma in an endemic goitre area. A comparative analysis between minimally invasive and widely invasive follicular thyroid carcinoma was performed. The medical records of all patients who underwent thyroidectomy from October 1998 to April 2012 for thyroid malignancies were reviewed. Those who had a histological diagnosis of follicular carcinoma were included. Among 5203 patients, 130 (2.5%) were included. Distant metastases at presentation were observed in four patients. Sixty-six patients had a minimally invasive follicular carcinoma and 64 a widely invasive follicular carcinoma. In 63 patients an oxyphilic variant was registered. Minimally/widely invasive ratio was 41/26 for usual follicular carcinoma and 25/38 for oxyphilic variant (P < 0.05). Patients with widely invasive tumors had larger tumors (P < 0.001) and more frequently oxyphilic variant (P < 0.05) than those with minimally invasive tumours. No significant difference was found between widely invasive and minimally invasive tumors and between usual follicular carcinoma and oxyphilic variant regarding the recurrence rate (P = NS). The incidence of follicular thyroid carcinoma is much lower than classically retained. Aggressive treatment, including total thyroidectomy and radioiodine ablation, should be proposed to all patients.

The Morphology of Nasal Polyps in Different Age Groups: Histopathological Features.

BACKGROUND: Nasal polyps (NPs) represent the end-stage manifestation of chronic rhinosinusitis (CRS), a relatively common pathological condition encountered in all ages of life. METHODOLOGY: The aim of our study was to evaluate the histological features and inflammatory cellular components of NPs in a retrospective cohort (143 cases) of pediatric, adult and elderly populations in order to discuss the possible morphological age-related differences statistically documented. RESULTS: In the pediatric group, the inflammatory infiltrate presented many eosinophils mixed with lymphocytes, while in the adult population, lymphocytes and plasma cells were mainly evident, frequently with a perivascular distribution or with the formation of subepithelial lymphoid nodules. In the elderly population, inflammation was less evident and was associated with cavernous-like angecthatic structures with thrombotic stratification. Nearly all morphological findings exhibited statistically significant values among differently aged subgroups. CONCLUSIONS: Our results support the presence of histological specificities of NPs at different ages of life, providing new insight into the etiopathogenesis of NPs. The future role of biological therapies, mainly in cases refractory to already available standard medical and surgical treatments, may be analyzed by a prospective study using a larger cohort with a long-term evaluation also in relation to a possible relapse.

Case Report: Plummer's adenoma in Prader-Willi syndrome.

Thyroid nodules in children are less common than in adults but they are approximately two- to three-fold more likely to be malignant in children. Among thyroid nodular diseases, Plummer's adenoma occurs very rarely in pediatrics, and currently, there is no literature providing evidence of this diagnosis in patients with Prader-Willi syndrome (PWS). We report the case of a 9-year-old Caucasian boy affected by PWS presenting with a rapidly growing palpable mass in the thyroid lodge associated with subclinical hyperthyroidism. Laboratory and other examinations (thyroid ultrasound, fine-needle aspiration of the nodule, and scintigraphy) were strongly suggestive for Plummer's adenoma; therefore, the patient underwent left hemithyroidectomy surgery, and anatomo-pathological examination confirmed the diagnosis. Our case describes the first evidence of an isolated follicular adenoma in children with PWS. Surgery is the only therapeutic option in younger children. Further evidence is needed to assess the possible correlation between these two conditions and the existence of potential risk factors.