Diagnostica cito-istologica dei noduli tiroidei:uno studio multicentrico

La citologia agoaspirativa con ago sottile (FNA) rappresenta uno strumento diagnostico fondamentale nella gestione clinica dei pazienti con noduli tiroidei. Tuttavia, come dimostrato dai dati della letteratura, quest’ultima mostra una performance diagnostica molto variabile ed è gravata da una percentuale di falsi negativi pari al 7%. Altro limite ben noto di questa metodica è l’elevata percentuale (24%) di FNAs con risultato indeterminato, il 70%-80% dei quali, risulta essere benigno all’esame istologico post-operatorio. Abbiamo quindi intrapreso uno studio con lo scopo di sviluppare un test molecolare per migliorare la gestione clinica di questi pazienti. Nel collezionare tale materiale agoaspirativo e nell’analizzare i dati clinici associati abbiamo perseguito un triplice scopo: - Correlare i risultati citologici ed istologici per valutare la performance diagnostica della citologia agoaspirativa dei noduli tiroidei (senisibilita’, specificità, valore predittivo positivo e valore predittivo negativo) in uno studio di tipo prospettico. - Condurre una meta-analisi aggiornata della letteratura e comparare i dati così ottenuti con i nostri. - Confrontare le diagnosi istologiche effettuate da un panel di anatomopatologi di riferimento con quelle formulate dai patologi locali. Materiali e metodi Performance diagnostica. Il materiale agoaspirativo selezionato da vari centri è stato diviso in due gruppi: - Gruppo A : materiale prospettico. FNAs provenienti da 21 cliniche (16 statunitensi-non accademiche, 3 statunitensi-accademiche, 2 accademiche non-statunitensi), in un periodo compreso tra agosto 2008-gennaio 2010. - Gruppo B: materiale retrospettivo. FNAs proveniente dagli archivi di 2 cliniche accademiche. Le diagnosi citologiche (gruppo A) sono quindi state comparate con le diagnosi istologiche formulate dai patologi locali al fine di valutarne la perfomance diagnostica (sensibilita’ specificità, valore predittivo positivo valore predittivo negativo e percentuale di falsi negativi) Concordanza diagnostica. Una parte dei preparati istologici e’ stata revisionata da due anatomopatologi di riferimento, il prof. Juan Rosai e la prof.ssa Virginia LiVolsi. I un primo momento, ogni esperto ha revisionato i casi indipendentemente, ovvero all’oscuro della diagnosi formulate dal patologo locale e dell’opinione dell’altro esperto. Successivamente i due patologi esperti hanno avuto la possibilità di discutere i casi nei quali vi era disaccordo, al fine di raggiungere una diagnosi di consenso. E’ stato quindi possibile valutare la concordanza diagnostica tra esperti e tra esperti vs patologi locali. Metanalisi della lettera Sono stati selezionati dalla letteratura studi incentrati sul confronto cito-istologico nella diagnostica tiroidea e che rispondessero ai seguenti criteri: • Lo studio doveva essere condotto sulla popolazione statunitense. • I prelievi dei noduli non palpabili dovevano essere eseguiti sotto guida ecografica. • Lo studio doveva includere più di 150 controlli chirurgici. I vari studi sono stati divisi in accademici e non-accademici in base all’istituto di provenienza. Risultati Sono stati selezionati 1501 campioni citologici (gruppo A + gruppo B) ottenuti da 1285 pazienti con età compresa tra i 18-94 anni (età media = 52 anni), l’85% dei quali di sesso femminile. 606 esami citologici (gruppo A + gruppo B) avevano un controllo istologico e di questi , 221 sono stati rivalutati dai 2 anatomopatologi esperti. Dei 1501 campioni citologici, 753 (613 pazienti ) appartiene al gruppo A (studio prospettico). Circa il 99% delle FNAs sono state eseguite sotto guida ecografica. La performance diagnostica della citologia agoaspirativa tiroidea ottenuta sul nostro materiale è risultata comparabile con quando osservato nella meta-analisi della letteratura. In particolare le percentuali di noduli maligni all’esame istologico tra i citologici “indeterminati” e “maligni” è risultata essere rispettivamente del 34% e 98% quindi sovrapponibile a quanto osservato nella meta-analisi della letteratura (rispettivamente 34% e 98%). Per quanto riguarda il tasso di malignità tra i citologici benigni abbiamo osservato una percentuale di falsi negativi maggiore tra i nostri agoaspirati rispetto alla meta-analisi della letteratura (11% vs 6%). Nell’ambito dell’analisi falsi negativi riscontrati in letteratura, abbiamo inoltre osservato una percentuale differente tra gli studi effettuati presso centri accademici rispetto ai centri non-accademici (2% vs 10%). Anche le percentuali di agoaspirati per ogni categoria diagnostica citologica, osservate nello studio prospettico (gruppo A), sono risultate simili a quanto osservato nella meta-analisi. La percentuale di discordanza diagnostica istologica (benigno vs maligno) è risultata maggiore nel confronto tra patologi locali vs diagnosi di consenso degli esperti (11%) rispetto a quanto osservato tra esperti sia pre- (8%) che post-confronto (3%). Conclusioni La percentuale post-operatoria di malignità osservata nel nostro studio è paragonabile a quanto osservato nella meta-analisi della letteratura. Quindi, sebbene le recenti linee guida abbiano cercato di standardizzare ed ottimizzare la tecnica di esecuzione e di interpretazione degli FNA tiroidei i risultati falsamente positivi e falsamente negativi rimangono un problema irrisolto. Inoltre, l’elevato numero di citologici indeterminati con diagnosi istologica di patologia benigna (66%), pone un interrogativo sulla corretta gestione clinica di questi pazienti. Data la variabilità osservata nel formulare le diagnosi istologiche, nuovi test molecolari sviluppati con l’intento di migliorare la gestione clinica dei pazienti con patologia tiroidea, dovranno comprendere nella loro elaborazione la revisione istologica da parte di esperti in patologia tiroidea

Inter-Observer Variation in the Pathologic Identification of Extranodal Extension in Nodal Metastasis from Papillary Thyroid Carcinoma

Background: Extranodal extension (ENE) in lymph node metastases has been shown to worsen the prognosis of papillary thyroid cancer (PTC). Despite the clinical significance of ENE, there are no stringent criteria for its microscopic diagnosis, and its identification is subject to inter-observer variability. The objective of this study was to determine the level of agreement among expert pathologists in the identification of ENE in PTC cases. Methods: Eleven expert pathologists from the United States, Italy, and Canada were asked to review 61 scanned slides of representative permanent sections of PTC specimens from Mount Sinai Beth Israel Medical Center in New York. Each slide was evaluated for the presence of ENE. The pathologists were also asked to report the criteria they use to identify ENE. Results: The overall strength of agreement in identifying ENE was only fair (??=?0.35), and the proportion of observed agreement was 0.68. The proportions of observed agreement for the identification of perinodal structures (fat, nerve, skeletal, and thick-walled vessel involvement) ranged from 0.61 to 0.997. Conclusions: Overall agreement for the identification of ENE is poor. The lack of agreement results from both variation in pathologists' identification of features and disagreement on the histologic criteria for ENE. This lack of concordance may help explain some of the discordant information regarding prognosis in clinical studies when this feature is identified.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140272/1/thy.2015.0551.pd

Inter-Observer Variation in the Pathologic Identification of Minimal Extrathyroidal Extension in Papillary Thyroid Carcinoma

Background: Extrathyroidal extension (ETE) is a significant prognostic factor in papillary thyroid carcinoma (PTC). Minimal extrathyroidal extension (mETE) is characterized by involvement of the sternothyroid muscle or perithyroid soft tissue, and is generally identified by light microscope examination. Patients with mETE, identified pathologically, are automatically upstaged to pT3. However, the prognostic implications of mETE have been a source of controversy in the literature. Moreover, there is also controversy surrounding the identification of mETE on pathological specimens. The objective of this study was to determine the level of agreement among expert pathologists in the identification of mETE in PTC cases. Methods: Eleven expert pathologists from the United States, Italy, and Canada were asked to perform a review of 69 scanned slides of representative permanent sections of PTC specimens. Each slide was evaluated for the presence of mETE. The pathologists were also asked to list the criteria they use to identify mETE. Results: The overall strength of agreement for identifying mETE was slight (??=?0.14). Inter-pathologist agreement was best for perithyroidal skeletal muscle involvement (??=?0.46, moderate agreement) and worst for invasion around thick-walled vascular structures (??=?0.02, slight agreement). In addition, there was disagreement over the constellation of histologic features that are diagnostic for mETE, which affected overall agreement for diagnosing mETE. Conclusions: Overall agreement for the identification of mETE is poor. Disagreement is a result of both variation in individual pathologists' interpretations of specimens and disagreement on the histologic criteria for mETE. Thus, the utility of mETE in staging and treatment of PTC is brought into question. The lack of concordance may explain the apparent lack of agreement regarding the prognostic significance of this pathologic feature.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140271/1/thy.2015.0508.pd

Agreement on endoscopic ultrasonography-guided tissue specimens: Comparing a 20-G fine-needle biopsy to a 25-G fine-needle aspiration needle among academic and non-academic pathologists

Background and Aim: A recently carried out randomized controlled trial showed the benefit of a novel 20-G fine-needle biopsy (FNB) over a 25-G fine-needle aspiration (FNA) needle. The current study evaluated the reproducibility of these findings among expert academic and non-academic pathologists. Methods: This study was a side-study of the ASPRO (ASpiration versus PROcore) study. Five centers retrieved 74 (59%) consecutive FNB and 51 (41%) FNA samples from the ASPRO study according to randomization; 64 (51%) pancreatic and 61 (49%) lymph node specimens. Samples were re-reviewed by five expert academic and five non-academic pathologists and rated in terms of sample quality and diagnosis. Ratings were compared between needles, expert academic and

Whole slide images technology: preliminary experience in clinical microbiology

Today the “whole slide images” (virtual slides) is an important tool also in clinical microbiology. Virtual microscopy consists of digitizing a glass slide acquiring hundred of tiles of areas of interest at different resolution levels, and assembling them in a structured file. We shortly report the key elements of this technology from the acquisition of the image using a scanner, to the broadcasting of virtual slides to a distant viewer over an internet connection

An infrastructure for precision medicine through analysis of big data

Abstract Background Nowadays, the increasing availability of omics data, due to both the advancements in the acquisition of molecular biology results and in systems biology simulation technologies, provides the bases for precision medicine. Success in precision medicine depends on the access to healthcare and biomedical data. To this end, the digitization of all clinical exams and medical records is becoming a standard in hospitals. The digitization is essential to collect, share, and aggregate large volumes of heterogeneous data to support the discovery of hidden patterns with the aim to define predictive models for biomedical purposes. Patients’ data sharing is a critical process. In fact, it raises ethical, social, legal, and technological issues that must be properly addressed. Results In this work, we present an infrastructure devised to deal with the integration of large volumes of heterogeneous biological data. The infrastructure was applied to the data collected between 2010–2016 in one of the major diagnostic analysis laboratories in Italy. Data from three different platforms were collected (i.e., laboratory exams, pathological anatomy exams, biopsy exams). The infrastructure has been designed to allow the extraction and aggregation of both unstructured and semi-structured data. Data are properly treated to ensure data security and privacy. Specialized algorithms have also been implemented to process the aggregated information with the aim to obtain a precise historical analysis of the clinical activities of one or more patients. Moreover, three Bayesian classifiers have been developed to analyze examinations reported as free text. Experimental results show that the classifiers exhibit a good accuracy when used to analyze sentences related to the sample location, diseases presence and status of the illnesses. Conclusions The infrastructure allows the integration of multiple and heterogeneous sources of anonymized data from the different clinical platforms. Both unstructured and semi-structured data are processed to obtain a precise historical analysis of the clinical activities of one or more patients. Data aggregation allows to perform a series of statistical assessments required to answer complex questions that can be used in a variety of fields, such as predictive and precision medicine. In particular, studying the clinical history of patients that have developed similar pathologies can help to predict or individuate markers able to allow an early diagnosis of possible illnesses

Gain of hTERC: A genetic marker of malignancy in oral potentially malignant lesions

Summary Oral squamous cell carcinoma (OSCC) is the most common oral cancer, and major efforts is being made to identify molecular markers capable to differentiate oral potentially malignant lesions (OPMLs) with indolent course from lesions with aggressive behavior. We undertook a study to evaluate if gain of the human telomerase RNA component (hTERC) gene in OPMLs could indicate lesions at high risk of developing OSCC. The study was performed on 30 OPMLs with long-term follow-up using a dual-color interphase fluorescence in situ hybridization (FISH) for hTERC status. Progression to malignancy was observed in 9 of 10 cases harboring hTERC gain and in 1 of 20 cases retaining a normal copy number of hTERC (P <.0001). Combining morphological grading and FISH analysis, all the cases with high-grade squamous intraepithelial lesion or carcinoma in situ harboring hTERC amplification progressed to OSCC, whereas none of the low-grade squamous intraepithelial lesions without hTERC gain progressed. Intermediate situations occurred. The data suggest that precise morphological evaluation together with FISH assessment for hTERC gain might pave the way to stratify OPMLs into high-risk and low-risk categories and could be helpful in selecting the most appropriate treatment