Second edition of the Milan System for Reporting Salivary Gland Cytopathology: Refining the role of salivary gland FNA.

The use of standardised reporting systems for non-gynaecologic cytopathology has made enormous gains in popularity during the past decade, including for thyroid fine-needle aspiration, urine cytology, serous effusions, pancreas, lymph nodes, lung and more. In February 2018, the first edition of the Atlas of the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was published. The MSRSGC defines six diagnostic fine-needle aspiration categories encompassing the spectrum of non-neoplastic, benign and malignant lesions of the salivary glands. The goal of the MSRSGC is to combine each diagnostic category with a defined risk of malignancy and a specific clinical and/or surgical management algorithm. Since its initial publication in 2018, more than 200 studies and commentaries have been published, confirming the role of the MSRSGC. The second edition of the MSRSGC, published in July 2023, includes refined risks of malignancy based on systematic reviews and meta-analyses, a new chapter summarising the use of salivary gland imaging, new advances in ancillary testing and updates in nomenclature.

An Overview of Pituitary Neuroendocrine Tumors (PitNET) and Algorithmic Approach to Diagnosis.

The diagnostic algorithm and nomenclature of pituitary neuroendocrine tumors have evolved over the past decade, beginning with simpler categorical schemes focused on histomorphologic features and moving to a more sophisticated lineage-specific categorization. This contemporary overview highlights a multimodal approach to pituitary neuroendocrine tumors with a focus on changes in nomenclature, classification, and subclassification; including, brief comments on treatment, and new guidelines for genetic screening, particularly for young patients with such neoplasms.

Salivary gland neoplasms in small biopsies and fine needle aspirations.

Salivary gland neoplasms are rare and represent a diverse group of head and neck tumors. Their diagnosis in limited cellularity specimens can be challenging as many of these have overlapping clinical, radiological presentation, and pathologic features. Fine needle aspiration and/or core biopsies are more of a norm than rarity to be performed preoperatively to provide invaluable information that can guide clinical management including surgery. Even though these limited specimens may not always provide a definitive diagnosis; they have high sensitivity in confirming primary neoplasia, assessing the tumor grade, and ruling out non-surgical disease. An algorithmic pattern based approach can help narrow the differential diagnosis; leading to a definitive diagnosis with the help of specific ancillary studies.

Consensus Statement by the American Association of Clinical Endocrinology (AACE) and the American Head and Neck Society Endocrine Surgery Section (AHNS) on Pediatric Benign and Malignant Thyroid Surgery.

OBJECTIVES: To provide a clinical disease state review of recent relevant literature and to generate expert consensus statements regarding the breadth of pediatric thyroid cancer diagnosis and care, with an emphasis on thyroid surgery. To generate expert statements to educate pediatric practitioners on the state-of-the-art practices and the value of surgical experience in the management of this unusual and challenging disease in children. METHODS: A literature search was conducted and statements were constructed and subjected to a modified Delphi process to measure the consensus of the expert author panel. The wording of statements, voting tabulation, and statistical analysis were overseen by a Delphi expert (J.J.S.). RESULTS: Twenty-five consensus statements were created and subjected to a modified Delphi analysis to measure the strength of consensus of the expert author panel. All statements reached a level of consensus, and the majority of statements reached the highest level of consensus. CONCLUSION: Pediatric thyroid cancer has many unique nuances, such as bulky cervical adenopathy on presentation, an increased incidence of diffuse sclerosing variant, and a longer potential lifespan to endure potential complications from treatment. Complications can be a burden to parents and patients alike. We suggest that optimal outcomes and decreased morbidity will come from the use of advanced imaging, diagnostic testing, and neural monitoring of patients treated at high-volume centers by high-volume surgeons.

American Association of Clinical Endocrinology And Associazione Medici Endocrinologi Thyroid Nodule Algorithmic Tool.

OBJECTIVE: The first edition of the American Association of Clinical Endocrinology/American College of Endocrinology/Associazione Medici Endocrinologi Guidelines for the Diagnosis and Management of Thyroid Nodules was published in 2006 and updated in 2010 and 2016. The American Association of Clinical Endocrinology/American College of Endocrinology/Associazione Medici Endocrinologi multidisciplinary thyroid nodules task force was charged with developing a novel interactive electronic algorithmic tool to evaluate thyroid nodules. METHODS: The Thyroid Nodule App (termed TNAPP) was based on the updated 2016 clinical practice guideline recommendations while incorporating recent scientific evidence and avoiding unnecessary diagnostic procedures and surgical overtreatment. This manuscript describes the algorithmic tool development, its data requirements, and its basis for decision making. It provides links to the web-based algorithmic tool and a tutorial. RESULTS: TNAPP and TI-RADS were cross-checked on 95 thyroid nodules with histology-proven diagnoses. CONCLUSION: TNAPP is a novel interactive web-based tool that uses clinical, imaging, cytologic, and molecular marker data to guide clinical decision making to evaluate and manage thyroid nodules. It may be used as a heuristic tool for evaluating and managing patients with thyroid nodules. It can be adapted to create registries for solo practices, large multispecialty delivery systems, regional and national databases, and research consortiums. Prospective studies are underway to validate TNAPP to determine how it compares with other ultrasound-based classification systems and whether it can improve the care of patients with clinically significant thyroid nodules while reducing the substantial burden incurred by those who do not benefit from further evaluation and treatment.

Hürthle-cell neoplasms of the thyroid: An algorithmic approach to pathologic diagnosis in light of molecular advances.

Our understanding of neoplasia is evolving at a rapid pace in these exciting times, where recent molecular pathology advances are reinforcing and fine tuning morphological divisions and classification. Thyroid gland neoplasia in general, and Hürthle-cell neoplasms in particular, are no exception in the current era of histopathology-molecular biology paradigm. In this review paper, we discuss the rationale that led pathologists in the past to separate Hürthle-cell neoplasms into its own dedicated diagnostic category, and provide an algorithmic approach to the differential diagnosis of oncocytic lesions of the thyroid. This review will also shed light on the current WHO classification of Hürthle-cell neoplasms in light of molecular advances that justify histopathologic distinctions.

Salivary Gland Fine Needle Aspiration and Introduction of the Milan Reporting System.

Fine needle aspiration (FNA) is a well-established procedure for the diagnosis and management of salivary gland lesions despite challenges imposed by their diversity, complexity, and cytomorphologic overlap. Until recently, the reporting of salivary gland FNA specimens was inconsistent among different institutions throughout the world, leading to diagnostic confusion among pathologists and clinicians. In 2015, an international group of pathologists initiated the development of an evidence-based tiered classification system for reporting salivary gland FNA specimens designated the "Milan System for Reporting Salivary Gland Cytopathology" (MSRSGC) that culminated with the publication of the MSRSGC Atlas in February 2018. The MSRSGC consists of 6 diagnostic categories, which incorporate the morphologic heterogeneity and overlap among various non-neoplastic, benign, and malignant lesions of the salivary glands. In addition, each diagnostic category is associated with a risk of malignancy and management recommendations. The main goal of the MSRSGC is to improve communication between cytopathologists and treating clinicians, while also facilitating cytologic-histologic correlation, sharing of data from different laboratories for quality control, and research. Herein, we review the current status of salivary gland cytology and the role of MSRSGC in providing a framework for reporting salivary gland lesions.

The utility of the Milan System as a risk stratification tool for salivary gland fine needle aspiration cytology specimens.

OBJECTIVE: To perform a retrospective investigation of our institutional experience with salivary gland fine needle aspirations (FNA) through the framework of The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) and assess the risks of neoplasm and malignancy for each diagnostic category. METHODS: All salivary gland FNAs performed from January 2009 to December 2016 were retrospectively categorised according to the MSRSGC. When available, pre-operative cytological results were correlated with subsequent histological follow-up. RESULTS: In total, 893 FNAs were reviewed. The specimens were retrospectively classified as nondiagnostic (ND: 13.5%), non-neoplastic (NN: 16.1%), atypia of undetermined significance (AUS: 10.8%), benign neoplasm (BN: 34.9%), salivary gland neoplasm of uncertain malignant potential (SUMP: 8.2%), suspicious for malignancy (SM: 2.7%) and malignant (M: 13.8%). Histological follow-up was available for 429 cases (48%); the majority (68.1%) were benign. The risks of neoplasm and malignancy for each category were as follows: ND: 64.5%, 16.1%; NN: 42.9%, 17.9%; AUS: 79.6%, 30.6%; BN: 100%, 2.2%; SUMP: 100%, 46.6%; SM: 94.7%, 78.9%; and M: 100%, 98.5%. CONCLUSIONS: The MSRSGC is a useful classification scheme for stratifying salivary gland lesions according to their associated risk of malignancy and guiding clinicians toward appropriate management. Diagnostic pitfalls are seen in a small proportion of cases and a multidisciplinary approach for assessing salivary gland pathology is essential in their evaluation.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a review for pathologists.

The rising incidence of papillary thyroid carcinoma is linked in part to inclusion of noninvasive follicular variant of papillary thyroid carcinoma. Despite its designation as carcinoma, noninvasive follicular variant of papillary thyroid carcinoma appears to be exceptionally indolent, often over treated by current treatment practices. Additionally, criteria for diagnosis have historically been subjective and challenging. Recently, an international multidisciplinary collaborative group performed a clinicopathologic survey of such cases with extended follow-up and concluded based on the outcome data that a revision in nomenclature was warranted, proposing 'Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP).' This monograph is a synopsis and guide for pathologists on NIFTP and focuses on histologic features, including inclusion and exclusion criteria used to define NIFTP, as well as grossing guidelines, reporting practices, and potential diagnostic limitations.

Special types of thyroid carcinoma.

This article reviews the small percentage of thyroid tumours that are not classified as classic papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma. It includes subtypes of papillary thyroid carcinoma, including, tall-cell, hobnail/micropapillary, columnar cell, diffuse sclerosing and solid variants. Poorly differentiated carcinoma, high-grade carcinoma and anaplastic thyroid carcinoma are reviewed. Also discussed are entities that are unusual but need to be recognized as primary thyroid neoplasms, i.e. mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia, and mammary analogue secretory carcinoma/secretory carcinoma. The pathological features and prognostic factors are described; a brief review of molecular correlates of these neoplasms is included.

Thyroid sclerosing mucoepidermoid carcinoma with eosinophilia: a clinicopathologic and molecular analysis of a distinct entity.

Sclerosing mucoepidermoid carcinoma with eosinophilia is a rare thyroid neoplasm of uncertain pathogenesis that resembles salivary gland mucoepidermoid carcinoma. This multi-institutional study characterizes the clinicopathologic and molecular features of this tumor by utilizing next-generation sequencing to assess common mutations and gene fusions involved in thyroid carcinogenesis as well as fluorescence in-situ hybridization for MAML2 translocations typical of salivary gland mucoepidermoid carcinoma. Nine cases (6 females and 3 males, mean age: 59 years, range 30-77 years) were identified. All cases were comprised of nests and strands of tumor cells with both squamous and mucinous differentiation embedded in a fibrohyaline stroma with an inflammatory infiltrate replete with eosinophils. All cases were p63 positive, thyroglobulin negative and showed variable expression of TTF-1. All nine cases were negative for MAML2 rearrangements. Five cases successfully tested by next-generation sequencing (ThyroSeq v.2 assay) were negative for mutations and translocations commonly involved in thyroid carcinogenesis. NTRK1 showed overexpression but no evidence of translocation. On follow-up, one patient died of persistent disease, whereas one of four remaining patients with available follow-up (mean: 7.3 years, range 4-11 years) demonstrated recurrence at 4 years. Thus, we show that sclerosing mucoepidermoid carcinoma with eosinophilia appears molecularly and morphologically distinct from follicular and C-cell-derived thyroid tumors as well as from salivary gland mucoepidermoid carcinoma. The overall and recurrence-free survival for these patients may be lower than for other well-differentiated thyroid cancers.

The Molecular Landscape of Noninvasive Follicular Thyroid Neoplasm With Papillary-like Nuclear Features (NIFTP): A Literature Review.

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.

MANAGING THYROID TUMORS DIAGNOSED AS NON-INVASIVE FOLLICULAR TUMOR WITH PAPILLARY LIKE NUCLEAR FEATURES (NIFTP).

This commentary summarizes the history and reclassification of noninvasive follicular thyroid tumor with papillary like nuclei (NIFTP). The salient histopathologic features, which are based on immunohistochemical and molecular profiles and serve as inclusion and exclusion criteria are reviewed. The authors also provide their own point of view regarding the practical issues and possible concerns that may be raised by both clinicians and patients based on the diagnosis of NIFTP.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE COMMENTARY: MANAGING THYROID TUMORS DIAGNOSED AS NONINVASIVE FOLLICULAR THYROID NEOPLASM WITH PAPILLARY-LIKE NUCLEAR FEATURES.

This commentary summarizes the history and reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclei (NIFTP). It reviews the salient histopathologic features that are based on immunohistochemical and molecular profiles and serve as inclusion and exclusion criteria. The authors also provide their own point of view regarding the practical issues and possible concerns that may be raised by both clinicians and patients based on the diagnosis of NIFTP. ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists EFVPTC = encapsulated FVPTC FNA = fine-needle aspiration FVPTC = follicular variant of papillary thyroid carcinoma NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features PTC = papillary thyroid carcinoma.

Patient Safety Curriculum for Anatomic Pathology Trainees: Recommendations Based on Institutional Experience.

Because of the unique systems and skills involved in patient care by the pathologist, it is challenging to design and implement relevant training in patient safety for pathology trainees. We propose a patient safety curriculum for anatomic pathology (AP) residents based on our institutional experience. The Hospital of the University of the Pennsylvania employs a self-reporting safety database. The occurrences from July 2013 to June 2015 recorded in this system that involved the division of AP were reviewed and cataloged as preanalytic, analytic, and postanalytic. The distribution of these occurrences was then used to create a framework for curriculum development in AP. We identified areas in which trainees are involved in the identification and prevention of common patient safety errors that occur in our AP department. Using these data-proven target areas, and employing current Accreditation Council for Graduate Medical Education recommendations and patient safety literature, a strategy for delivering relevant patient safety training is proposed. Teaching patient safety to pathology trainees is a challenging, yet necessary, component of AP training programs. By analyzing the patient safety errors that occur in the AP department, relevant and actionable training can be developed. This provides quality professional development and improves overall performance as trainees are integrated into laboratory systems.

Preoperative diagnosis of benign thyroid nodules with indeterminate cytology.

BACKGROUND: Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspiration are not clearly benign or malignant. Patients with cytologically indeterminate nodules are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes has shown promise in improving preoperative risk assessment. METHODS: We performed a 19-month, prospective, multicenter validation study involving 49 clinical sites, 3789 patients, and 4812 fine-needle aspirates from thyroid nodules 1 cm or larger that required evaluation. We obtained 577 cytologically indeterminate aspirates, 413 of which had corresponding histopathological specimens from excised lesions. Results of a central, blinded histopathological review served as the reference standard. After inclusion criteria were met, a gene-expression classifier was used to test 265 indeterminate nodules in this analysis, and its performance was assessed. RESULTS: Of the 265 indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92% sensitivity; 95% confidence interval [CI], 84 to 97), with a specificity of 52% (95% CI, 44 to 59). The negative predictive values for "atypia (or follicular lesion) of undetermined clinical significance," "follicular neoplasm or lesion suspicious for follicular neoplasm," or "suspicious cytologic findings" were 95%, 94%, and 85%, respectively. Analysis of 7 aspirates with false negative results revealed that 6 had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule. CONCLUSIONS: These data suggest consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results. (Funded by Veracyte.).

Oncocytic lesions of the neuroendocrine system.

This paper reviews the pathologic features of lesions which are oncocytic and involve classic endocrine organs. The history of the oncocytic cell, its morphologic and ultrastructural features, and important immunohistochemical findings are reviewed. Oncocytic proliferations including non-neoplastic and neoplastic of the thyroid, parathyroid, adrenal (both cortex and medulla), and pituitary are described. Their clinical relevance, functional capacity and capability, and where appropriate, prognostic implications are discussed. Important and relevant molecular biological information is included where appropriate.

A prospective assessment defining the limitations of thyroid nodule pathologic evaluation.

BACKGROUND: Clinical management of thyroid neoplasms is based on light microscopic diagnosis, but its accuracy and precision are poorly defined. OBJECTIVE: To assess inter- and intraobserver variability of preoperative cytopathologic and postoperative histopathologic thyroid diagnoses. DESIGN: Samples were collected in a prospective, multicenter trial validating a gene expression classifier between June 2009 and December 2010. SETTING: 14 academic and 35 community clinical sites. PATIENTS: 653 patients with 776 surgically resected thyroid nodules of 1 cm or greater. MEASUREMENTS: Intraobserver concordance among 2 or more central histopathologists who independently read histopathology slides was calculated. Interobserver concordance between the diagnoses made by the central histopathologists and those made by local pathologists were calculated. Intra- and interobserver concordance for cytopathology was similarly calculated by comparing diagnoses made by local pathologists with those made by a central panel of 3 cytopathologists. RESULTS: Concordance on the histopathologic distinction between benign and malignant diagnoses was 91% comparing local with central histopathologists and 90% comparing 2 central histopathologists. Using the 6-category Bethesda System, 64.0% of diagnoses made by local and central cytopathologists and 74.7% of intraobserver diagnoses were concordant. Central cytopathologists made fewer indeterminate diagnoses than local pathologists (41.2% vs. 55.0%). LIMITATIONS: Many local pathologists did not use the Bethesda System, so their reports were translated to allow comparison. The study required histopathology, and the study population and specimens did not encompass all newly evaluated patients with a thyroid nodule. CONCLUSION: Substantial inter- and intraobserver variability exists in the cytopathologic and histopathologic evaluation of thyroid nodules, confirming an inherent limitation of visual microscopic diagnosis. PRIMARY FUNDING SOURCE: Veracyte.

Pitfalls in Thyroid Fine-Needle Aspiration Cytopathology: An Approach to Atypical Findings.

BACKGROUND: Thyroid nodules are prevalent among the general population, thus imposing substantial demands upon healthcare providers to establish effective management paradigms when investigating these lesions. A pivotal component in the diagnostic process involves the cytomorphological evaluation of fine-needle aspiration (FNA) specimens extracted from the nodule under scrutiny. This examination serves the critical purpose of enabling a comprehensive assessment for the risk of either a neoplasm or malignancy, thereby providing the clinical team with the requisite information to render decisions regarding potential surgical intervention and/or a structured clinical follow-up. A subset of FNA specimens obtained from the thyroid gland present a vexing challenge for interpretation and cannot be classified based on cytomorphology as either benign or malignant and are classified as "indeterminate" for neoplasm or malignancy. The indeterminate thyroid FNA diagnosis in the third iteration of the Bethesda classification is termed as "atypia of undetermined significance" (AUS). SUMMARY: The thyroid FNA specimens classified as "atypical" constitute a perplexing category, necessitating considerations such as repeated cytological evaluations, supplementary molecular analyses, diagnostic lobectomy, or vigilant surveillance. This review article draws upon the most recent Bethesda classification guidelines and delineates various potential pitfalls encountered during the interpretation of atypia observed in thyroid fine-needle aspiration and histopathologic counterparts. Additionally, it proffers strategic algorithms devised to effectively navigate these diagnostic challenges. KEY MESSAGES: It is important to recognize the value of an integrated approach when triaging AUS lesions, considering various clinical, morphological, and sometimes also immunocytochemical or molecular features.