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Tall cell papillary carcinoma (TCPC) and insular carcinoma (IC) are variants of thyroid carcinoma that are considered to be more aggressive than well differentiated papillary or follicular carcinoma. To determine the clinical significance of these diagnoses, we evaluated 65 patients with these tumors. There were 30 TCPCs, 27 ICs, and 8 ICs or TCPCs with focal anaplastic carcinoma (FAC). Forty-two patients (27 TCPCs, 14 ICs, and 1 FAC) are alive and free of disease. Nine patients with IC are alive with distant metastases. Ten patients (2 TCPCs, 2 ICs, and 7 FACs) died of disease. Univariate analysis of disease-free interval determined that, as for all thyroid carcinomas, patient age, tumor size, extrathyroidal extension, and lymph node metastases were significant for prognosis. ICs did significantly worse than TCPCs. Focal anaplastic dedifferentiation predicted a worse prognosis. Multivariate analysis for disease-free interval showed age, number of lymph node metastases, and tumor type to be significant. Analysis of the same factors for prediction of mortality showed that TCPC and IC were not significantly different. These data suggest that TCPC is less aggressive than IC, which often results in disseminated disease. Focal AC predicts poor survival. [ABSTRACT FROM AUTHOR]

Tumors of adenohypophysial hormone-secreting cells, now classified as pituitary neuroendocrine tumors (PitNETs), have been subclassified based on cell differentiation. Normal adenohypophysial cells have three lineages of differentiation driven by the transcription factors PIT1, TPIT, and SF1 which are responsible for the regulation of hormone gene expression; PIT1 drives expression of GH, PRL, and TSH, TPIT is required for POMC expression that gives rise to ACTH, and SF1 is the transcription factor responsible for FSH and LH expression. The vast majority of PitNETs follow these three lineage differentiation pathways but rare PitNETs show either no lineage differentiation or express biomarkers of more than one lineage. The recent WHO classification continued the terminology "plurihormonal" for tumors that have features of more than one lineage but a better term is "multilineage" since some tumors may express more than one lineage-specific transcription factor without the hormones that are driven by those factors. Recent data indicate that tumors with expression of PIT1 and SF1 are the most common multilineage PitNETs. Here we report the existence of rare PitNETs that express TPIT and SF1. The 6 patients (5 female, 1 male; mean age 54.8 years; range 35-84 years) represent less than 1% of patients in our series of PitNETs. Most patients had clinically silent tumors with no evidence of hormone excess and variable degrees of hypopituitarism; two had Cushing disease. All patients had macrotumors with a mean tumor size of 2.46 cm (range 1.1-5.0 cm). Crooke's hyaline change was identified in the nontumorous adenohypophysis of the two patients with Cushing disease. The mean Ki67 labeling index was 2.91% (range 2.03-3.94%). All tumors were negative for PIT1 and PIT1-lineage hormones (GH, PRL, and TSH). TPIT was focal in one tumor, and the remaining tumors had diffuse reactivity in more than 50% of tumor cells. SF1 expression was focal in 5 tumors and diffuse in one. Three tumors had variable expression of at least one gonadotropin (FSH or LH). GATA3 was expressed in two tumors. Variable ER-alpha expression was noted in three tumors. CAM5.2 was positive in all tumors. With the exception of two tumors causing Cushing disease, p27 expression was intact. Our study confirms that multilineage PitNETs expressing TPIT and SF1 occur but are extremely rare; they can be clinically non-functional or can cause Cushing disease. Irrespective of functional status of a PitNET, routine application of pituitary transcription factors is warranted to identify these tumors. Data on the molecular correlates and clinical significance are still needed for these rare multilineage PitNETs., Competing Interests: Declarations. Ethics Approval: Obtained from both institutions. Conflict of Interest: Dr. Sylvia L. Asa is a member of the Editorial Board of Endocrine Pathology. Dr. Ozgur Mete is the Editor-in-Chief of Endocrine Pathology. This article is handled by an independent Editor as per Springer Nature policies. All remaining authors have no conflicts of interest to declare., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid cancer, with a disease recurrence rate of around 20%. Lymphoid formations, which occur in nonlymphoid tissues during chronic inflammatory, infectious, and immune responses, have been linked with tumor suppression. Lymphoid aggregates potentially enhance the body's antitumor response, offering an avenue for attracting tumor-infiltrating lymphocytes and fostering their coordination. Increasing evidence highlights the role of lymphoid aggregate density in managing tumor invasion and metastasis, with a favorable impact noted on overall and disease-free survival (DFS) across various cancer types. In this study, we present a machine vision model to predict recurrence in different histologic subtypes of PTC using measurements related to peritumoral lymphoid aggregate density. We demonstrated that quantifying peritumoral lymphocytic presence not only is associated with better prognosis but also, along with tumor-infiltrating lymphocytes within the tumor, adds additional prognostic value in the absence of well-known second mutations including TERT. Annotations of peritumoral lymphoid aggregates on 171 well-differentiated PTCs in the Cancer Genome Atlas Thyroid Carcinoma (TCGA-THCA) data set were used to train a deep-learning model to predict regions of lymphoid aggregates across the entire tissue. The fractional area of the tissue regions covered by these lymphocytes was dichotomized to determine the following 2 risk groups: a significant and low density of peritumoral lymphocytes. DFS prognosticated using these risk groups via the Kaplan-Meier analysis revealed a hazard ratio (HR) of 2.51 (95% CI: 2.36, 2.66), tested on 170 new patients also from the TCGA-THCA data set. The prognostic performance of peritumoral lymphocyte aggregate density was compared against the univariate Kaplan-Meier analysis of DFS using the fractional area of intratumoral lymphocytes within the primary tumor with an HR of 2.04 (95% CI: 1.89, 2.19). Combining the lymphocyte features in and around the tumor yielded a statistically significant improvement in prognostic performance (HR, 3.17 [95% CI: 3.02, 3.32]) on training and were independently evaluated against 62 patients outside TCGA-THCA with an HR of 2.44 (95% CI: 2.19, 2.69). Multivariable Cox regression analysis on the validation set revealed that the density of peritumoral and intratumoral lymphocytes was prognostic independent of histologic subtype with a concordance index of 0.815., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid cancer, with the classical and follicular variants representing most cases. Despite generally favorable prognoses, approximately 10% of patients experience recurrence post-surgery and radioactive iodine therapy. Attempts to stratify risk of recurrence have relied on gene expression-based prognostic and predictive signatures with a focus on mutations of well-known driver genes, while hallmarks of tumor morphology have been ignored., Objectives: We introduce a new computational pathology approach to develop prognostic gene signatures for PTC that is informed by quantitative features of tumor and immune cell morphology., Methods: We quantified nuclear and immune-related features of tumor morphology to develop a pathomic signature, which was then used to inform an RNA-expression signature model provides a notable advancement in risk stratification compared to both standalone and pathology-informed gene-expression signatures., Results: There was a 17.8% improvement in the C-index (from 0.605 to 0.783) for 123 cPTCs and 15% (from 0.576 to 0.726) for 38 fvPTCs compared to the standalone gene-expression signature. Hazard ratios also improved for cPTCs from 0.89 (0.67,0.99) to 4.43 (3.65,6.68) and fvPTC from 0.98 (0.76,1.32) to 2.28 (1.87,3.64). We validated the image-based risk model on an independent cohort of 32 cPTCs with hazard ratio 1.8 (1.534,2.167)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. The authors declare the following competing interests: Dr. Madabhushi is an equity holder in Picture Health, Elucid Bioimaging, and Inspirata Inc. Currently he serves on the advisory board of Picture Health, Aiforia Inc, and SimBioSys. He also currently consults for SimBioSys. He also has sponsored research agreements with AstraZeneca, Boehringer-Ingelheim, Eli-Lilly and Bristol Myers-Squibb. His technology has been licensed to Picture Health and Elucid Bioimaging. He is also involved in 3 different R01 grants with Inspirata Inc. He also serves as a member for the Frederick National Laboratory Advisory Committee. Dr Asa is on the Medical Advisory Boards of Leica Biosystems and Ibex Medical Analytics. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Multiple endocrine neoplasms are a feature of multiple endocrine neoplasia (MEN) syndromes types 1, 2, 4, and 5. However, the ileum is not usually involved in these disorders. We report a series of patients with neuroendocrine tumors (NETs) involving both the pancreas and the ileum. We searched the laboratory information system and personal consultation records of the authors from 2019 to 2023 for patients who had neuroendocrine tumors (NETs) involving both the pancreas and ileum. In a series of 846 patients, we identified 4 patients with pancreatic and ileal NETs, 2 female and 2 male, ages 52 to 75. Two female patients had primary EC cell tumors of the ileum with metastasis to the pancreas that showed expression of CDX2 and serotonin similar to the ileal primary tumors. Two males had primary lesions in the 2 sites with different immunoprofiles; the ileal tumors expressed CDX2 and serotonin and were negative for ARX, whereas the pancreatic tumors expressed ARX, glucagon, and pancreatic polypeptide and were negative for CDX2 and serotonin. In both male patients, the nontumorous pancreas showed preneoplastic changes in the endocrine elements, suggesting germline predisposition to endocrine neoplasia. Testing for known genetic alterations underlying MEN syndromes has not identified a genetic alteration that can be implicated in the development of NETs in both pancreas and ileum. Our series indicates the rare occurrence of NETs in both the pancreas and ileum and emphasizes the importance of using the correct biomarkers to distinguish metastasis from primary neoplasms at the different sites. The rare occurrence of primary ileal and pancreatic NETs may represent a novel MEN syndrome with as yet unknown germline predisposition., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The classification and management of neuroendocrine neoplasms (NENs) arising in the tubular gastrointestinal (GI) tract and pancreas have significantly evolved over the last decades. In the latest WHO classification published in 2022, NENs are separated regardless of their primary origin into two main groups: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The substantial changes in the grading system changed the definition of grade 3 to include high-grade well-differentiated NETs (G3-NETs), and poorly differentiated NECs (-NECs). Although these two subgroups are considered high grades with Ki-67 >20%, they have different genomic profiles, prognosis, and clinical behavior, which critically influence their treatment strategies. The available clinical trial data to guide therapy of these high-grade subgroups are extremely limited, which impacts their management. In this review, we will summarize the current advances in the multidisciplinary approach for the management of high-grade gastroenteropancreatic NENs (GEP-NENs) including G3-NETs and NECs.

Appendiceal neuroendocrine tumors (NETs) are common and often are identified as incidental lesions at the time of appendectomy. The guidelines for management are based on tumor size, degree of invasion, and the Ki67 proliferation index. Most small bowel NETs are composed of serotonin-producing EC-cells, but there are multiple other neuroendocrine cell types. In the rectum, there are L-cell tumors that express peptide YY (PYY), glucagon-like peptides (GLPs), and pancreatic polypeptide (PP); they are thought to have a better prognosis than serotonin-producing tumors. We investigated whether the appendix has distinct neuroendocrine tumor types based on cell type and whether that distinction has clinical significance. We collected 135 appendiceal NETs from the pathology archives of UHN Toronto and UHCMC (Cleveland). We analyzed the expression of biomarkers including CDX2, SATB2, PSAP, serotonin, glucagon (that detects GLPs), PYY, and pancreatic polypeptide (PP) and correlated the results with clinicopathologic parameters. Immunohistochemistry identified three types of appendiceal NETs. There were 75 (56%) classified as EC-cell tumors and 37 (27%) classified as L-cell tumors; the remaining 23 (17%) expressed serotonin and one of the L-cell biomarkers and were classified as mixed. EC-cell tumors were significantly larger with more extensive invasion involving the muscularis propria, subserosa, and mesoappendix compared with L-cell tumors. Mixed tumors were intermediate in all of these parameters. Both EC-cell and mixed tumors had lymphatic and/or vascular invasion while L-cell tumors had none. Unlike EC-cell NETs, L-cell tumors were not associated with lymph node metastasis. Tumor type correlated with pT stage and the only patient with distant metastatic disease in this series had an EC-cell tumor. Our study confirms that appendiceal NETs are not a homogeneous tumor population. There are at least three types of appendiceal NET, including EC-cell, L-cell, and mixed tumors. This information is important for surveillance of patients, as monitoring urinary 5HIAA levels is only appropriate for patients with serotonin-producing tumors, whereas measurement of GLPs and/or PP is more appropriate for patients with L-cell tumors. Our data also show that tumor type is of significance with EC-cell tumors exhibiting the most aggressive behavior., (© 2024. The Author(s).)

Background: The adoption of digital pathology has transformed the field of pathology, however, the economic impact and cost analysis of implementing digital pathology solutions remain a critical consideration for institutions to justify. Digital pathology implementation requires a thorough evaluation of associated costs and should identify and optimize resource allocation to facilitate informed decision-making. A dynamic cost calculator to estimate the financial implications of deploying digital pathology systems was needed to estimate the financial effects on transitioning to a digital workflow., Methods: A systematic approach was used to comprehensively assess the various components involved in implementing and maintaining a digital pathology system. This consisted of: (1) identification of key cost categories associated with digital pathology implementation; (2) data collection and analysis of cost estimation; (3) cost categorization and quantification of direct and indirect costs associated with different use cases, allowing customization of each factor based on specific intended uses and market rates, industry standards, and regional variations; (4) opportunities for savings realized by digitization of glass slides and (5) integration of the cost calculator into a unified framework for a holistic view of the financial implications associated with digital pathology implementation. The online tool enables the user to test various scenarios specific to their institution and provides adjustable parameters to assure organization specific relatability., Results: The Digital Pathology Association has developed a web-based calculator as a companion tool to provide an exhaustive list of the necessary concepts needed when assessing the financial implications of transitioning to a digital pathology system. The dynamic return on investment (ROI) calculator successfully integrated relevant cost and cost-saving components associated with digital pathology implementation and maintenance. Considerations include factors such as digital pathology infrastructure, clinical operations, staffing, hardware and software, information technology, archive and retrieval, medical-legal, and potential reimbursements. The ROI calculator developed for digital pathology workflows offers a comprehensive, customizable tool for institutions to assess their anticipated upfront and ongoing annual costs as they start or expand their digital pathology journey. It also offers cost-savings analysis based on specific user case volume, institutional geographic considerations, and actual costs. In addition, the calculator also serves as a tool to estimate number of required whole slide scanners, scanner throughput, and data storage (TB). This tool is intended to estimate the potential costs and cost savings resulting from the transition to digital pathology for business plan justifications and return on investment calculations., Conclusions: The digital pathology online cost calculator provides a comprehensive and reliable means of estimating the financial implications associated with implementing and maintaining a digital pathology system. By considering various cost factors and allowing customization based on institution-specific variables, the calculator empowers pathology laboratories, healthcare institutions, and administrators to make informed decisions and optimize resource allocation when adopting or expanding digital pathology technologies. The ROI calculator will enable healthcare institutions to assess the financial feasibility and potential return on investment on adopting digital pathology, facilitating informed decision-making and resource allocation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Endocrine cells responsible for hormone secretion are found in virtually every organ system. The diverse neoplasms arising from endocrine cells in the female reproductive tract are not well recognized as a distinct component of endocrine oncology. Here, we integrate cellular origins with native anatomical residence to help classify neoplasms of this system. The neoplasms include steroidogenic tumors that arise usually in ovarian stroma, neuroendocrine neoplasms that can arise from normal neuroendocrine cells throughout the female reproductive tract or in ovarian germ cell tumors, and thyroid follicular cell proliferations that are exclusively a component of an ovarian teratoma and may be malignant. The neuroendocrine neoplasms run the full spectrum from indolent neuroendocrine tumors to aggressive poorly differentiated neuroendocrine carcinomas. While many of these lesions are identified as incidental findings in surgically resected tissues, others present with inappropriate hormone excess. An important consideration is the distinction of primary disease from metastatic malignancy. Genetic disorders including those caused by germline mutations of the FOXL2, GNAS, DICER1, STK11 and MEN1 genes can present with primary endocrine neoplasms of the female reproductive tract., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Extra pulmonary high-grade poorly differentiated neuroendocrine carcinomas (EP-NECs) are rare tumors that usually arise in the gastrointestinal and genitourinary tracts. Primary neuroendocrine carcinoma of the breast (NEBC) is extremely rare, representing less than 0.1% of all breast cancers and less than 1% of neuroendocrine neoplasms. Consequently, they can be misdiagnosed as other types of breast cancer, however, proper immunohistochemical (IHC) studies can assist with making the correct diagnosis. Management of NEBC can be challenging given the paucity of evidence-based literature and should not routinely follow the therapeutic guidelines of other breast cancers. In this article, we review the current literature regarding the management of NEBC., 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 © 2024 Mohamed, Zeidalkilani, Asa, Trybula and Montero.)

Anaplastic thyroid carcinoma (ATC) often results from dedifferentiation of differentiated thyroid carcinoma (DTC), and the diagnosis is not difficult, as the tumor is seen to progress from a recognized DTC. However, in some cases, the diagnosis based on biopsy of limited tissue or resection of a completely undifferentiated tumor relies on immunohistochemical biomarkers and is usually a diagnosis of exclusion. To examine the biomarker profile of ATC and to determine whether divergent lineage markers can complicate this process, we examined the expression of a number of biomarkers in a series of ATCs. Cases retrieved from the department laboratory information system were included if there was evidence of an accurate diagnosis based on the presence of a coexisting or antecedent DTC or in cases where the immunoprofile was consistent with thyroid origin in a non-equivocal clinical setting. Questionable cases were excluded. We identified 36 cases for analysis. Tissue sections were stained for PAX8, TTF1, BRAFV600E, NRASQ61R, TRK, and p53, as well as p40, CDX2, SATB2, GATA3, CD117, CD163, SALL4, SMARCA4, PRAME, SOX10, ERG and HEPPAR1. As expected, all 36 ATCs were negative for TTF1 except for one showing focal, weak expression. Thirteen expressed PAX8 with variable intensity. BRAFV600E was positive in 10/34 tumors and equivocal in 3; NRASQ61R was positive in 12, and TRK was positive in 1 case. Staining for p53 was diffusely positive in 14 and completely negative in 19, with only 3 cases showing a wild-type pattern. We found aberrant expression of GATA3 in 11/36 cases, SATB2 in 8/36, CD117 in 2/35, and SALL4 in 1/30. CD163 expression was identified in tumor cells in 10/30 cases with variable intensity; in the other tumors, interpretation was obscured by abundant histiocytes. P40 was positive in 5 cases with squamoid morphology. CDX2 was negative in 35 tested cases. PRAME was identified in 1 of 33 cases. Stains for SOX10, ERG, and HEPPAR1 were negative in 33 cases. Twenty tested cases showed retained SMARCA4 expression. We conclude that ATCs express a number of divergent lineage markers that can cause diagnostic dilemmas, as they are also features of other tumors in the differential diagnosis of high-grade midline neck malignancies., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Transitioning from glass slide pathology to digital pathology for primary diagnostics requires an appropriate laboratory information system, an image management system, and slide scanners; it also reinforces the need for sophisticated pathology informatics including synoptic reporting. Previous reports have discussed the transition itself and relevant considerations for it, but not the selection criteria and considerations for the infrastructure., Objective: To describe the process used to evaluate slide scanners, image management systems, and synoptic reporting systems for a large multisite institution., Methods: Six network hospitals evaluated six slide scanners, three image management systems, and three synoptic reporting systems. Scanners were evaluated based on the quality of image, speed, ease of operation, and special capabilities (including z-stacking, fluorescence and others). Image management and synoptic reporting systems were evaluated for their ease of use and capacity., Results: Among the scanners evaluated, the Leica GT450 produced the highest quality images, while the 3DHistech Pannoramic provided fluorescence and superior z-stacking. The newest generation of scanners, released relatively recently, performed better than slightly older scanners from major manufacturers Although the Olympus VS200 was not fully vetted due to not meeting all inclusion criteria, it is discussed herein due to its exceptional versatility. For Image Management Software, the authors believe that Sectra is, at the time of writing the best developed option, but this could change in the very near future as other systems improve their capabilities. All synoptic reporting systems performed impressively., Conclusions: Specifics regarding quality and abilities of different components will change rapidly with time, but large pathology practices considering such a transition should be aware of the issues discussed and evaluate the most current generation to arrive at appropriate conclusions., Competing Interests: Declaration of Competing Interest Dr. Benzion Samueli is a recipient of a Fellowship Grant from the American Physicians Fellowship for Medicine in Israel (AFP). Prof. Sylvia Asa serves on medical advisory boards of Leica Biosystems, Ibex Medical Analytics and Iron Mountain. All remaining authors declare that they have no relevant financial interests. No funding was provided for the preparation of this manuscript. No AI was used in the preparation of this manuscript., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

The pathology of neoplasia tends to focus on the tumor that requires characterization, grading, and staging. However, nontumorous tissue surrounding the lesion can also provide information, particularly about pathogenetic mechanisms. In endocrine tissues, this takes the form of precursor lesions that characterize several genetic predisposition syndromes. In addition, because of the unique functional aspects of endocrine neoplasia, the nontumorous tissue provides evidence of hormone excess, with hyperplasia and/or atrophy and other involutional changes allowing the pathologist to confirm both hormone function by the tumor and the effects of medical therapies. In this article, we review the various clinically relevant features that should be assessed and reported to enhance clinical management of patients with endocrine neoplasms. For example, in thyroid there may be inflammatory thyroiditis or goiter of various etiologies; there may be C-cell hyperplasia either as a preneoplastic lesion in patients with genetic predisposition to medullary thyroid carcinoma or as a reactive phenomenon. Drug-induced changes can be seen in thyroid and adrenal cortex. In neuroendocrine tissues, the nontumorous tissues may show precursor lesions such as endocrine cell hyperplasia/dysplasia; there may be related or unrelated hyperplastic or neoplastic lesions. Some tissues, such as pituitary corticotrophs and adrenal cortex, develop changes that reflect feedback suppression by hormone excess that can serve as biomarkers of tumor functionality and provide enhanced clinicopathologic correlates., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Endocrine pathology comprises a spectrum of disorders originating in various sites throughout the body. Some disorders affect endocrine glands, and others arise from endocrine cells that are dispersed in non-endocrine tissues. Endocrine cells can broadly be classified as neuroendocrine, steroidogenic, or thyroid follicular cells; these three families have distinct embryologic origins, morphologic structure, and biochemical hormone synthetic pathways. Lesions affecting the endocrine system include developmental abnormalities, inflammatory processes that can be infectious or autoimmune, hypofunction with atrophy or hyperfunction caused by hyperplasia secondary to pathology in other sites, and neoplasia of many types. Understanding endocrine pathology requires knowledge of both structure and function, including the biochemical signaling pathways that regulate hormone synthesis and secretion. Molecular genetics has clarified sporadic and hereditary disease that is common in this field., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The assessment of cell differentiation in endocrine neoplasms involves not only the identification of a cell's structure and expression of specific transcription factors which regulate that cell, but also the identification of hormones and/or enzymes involved in hormone synthesis. The importance of this functional characterization is emphasized by the fact that the hormones serve as biomarkers for clinical surveillance to identify persistence, recurrence, or progression of disease. Sometimes, unusual patterns of hormone expression lead to unexpected clinical signs and symptoms. Loss of differentiated hormone production can be a sign of dedifferentiation as a tumor becomes more aggressive. In addition to prognostic information, cell differentiation can be predictive, since differentiated endocrine cells express targets for therapy, such as the sodium iodide symporter in thyroid cancers and somatostatin receptors in neuroendocrine tumors. The salient features of differentiation in the three main types of endocrine cells can be used to determine prognosis and to tailor management of patients with endocrine neoplasms., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Summary: This case report describes a rare presentation of ectopic Cushing's syndrome (CS) due to ectopic corticotropin-releasing hormone (CRH) production from a medullary thyroid carcinoma (MTC). The patient, a 69-year-old man, presented with symptoms of muscle weakness, facial plethora, and easy bruising. An inferior petrosal sinus sampling test (IPSS) demonstrated pituitary adrenocorticotrophic hormone (ACTH) secretion, but a whole-body somatostatin receptor scintigraphy (68Ga-DOTATOC PET/CT) revealed enhanced uptake in the right thyroid lobe which, in addition to a grossly elevated serum calcitonin level, was indicative of an MTC. A 18F-DOPA PET/CT scan supported the diagnosis, and histology confirmed the presence of MTC with perinodal growth and regional lymph node metastasis. On immunohistochemical analysis, the tumor cell stained positively for calcitonin and CRH but negatively for ACTH. Distinctly elevated plasma CRH levels were documented. The patient therefore underwent thyroidectomy and bilateral adrenalectomy. This case shows that CS caused by ectopic CRH secretion may masquerade as CS due to a false positive IPSS test. It also highlights the importance of considering rare causes of CS when diagnostic test results are ambiguous., Learning Points: Medullary thyroid carcinoma may secrete CRH and cause ectopic CS. Ectopic CRH secretion entails a rare pitfall of inferior petrosal sinus sampling yielding a false positive test. Plasma CRH measurements can be useful in selected cases.

PitNETs are usually restricted in their cytodifferentiation to only one of 3 lineages dictated by expression of the pituitary transcription factors (TFs) PIT1, TPIT, or SF1. Tumors that show lineage infidelity and express multiple TFs are rare. We searched the pathology files of 4 institutions for PitNETs with coexpression of PIT1 and SF1. We identified 38 tumors in 21 women and 17 men, average age 53 (range 21-79) years. They represented 1.3 to 2.5% of PitNETs at each center. Acromegaly was the presentation in 26 patients; 2 had central hyperthyroidism associated with growth hormone (GH) excess and one had significantly elevated prolactin (PRL). The remainder had mass lesions with visual deficits, hypopituitarism, and/or headaches. Tumor size ranged from 0.9 to 5 cm; all 7 lesions smaller than 1 cm were associated with acromegaly. Larger lesions frequently invaded the cavernous sinuses. Four cases represented a second attempt at surgical resection. PIT1 was usually diffusely positive but 5 cases had variable (patchy or focal) staining. SF1 reactivity was variable in intensity but diffuse in all but 2 cases. GATA3 data, available in 14 cases, identified diffuse positivity in 5 and focal staining in 1. GH was expressed in all but 5 tumors, PRL and thyrotropin (TSH) were expressed in 14 and 13, respectively, follicle-stimulating hormone (FSH) in 11 of 18, and luteinizing hormone (LH) in 4 of 17. Keratin staining patterns were diffuse perinuclear/membranous in 27, variable perinuclear in 4, and negative in 3; scattered fibrous bodies were seen in 5 and diffuse fibrous bodies in 1. Ki67 labeling index ranged from < 1 to 7.9%. In 3 cases, these tumors represented one of multiple synchronous PitNETs; a separate corticotroph tumor was seen in 2 patients and one patient had 2 additional discrete lesions, a sparsely granulated lactotroph, and a pure gonadotroph tumor comprising a triple tumor. PitNETs expressing PIT1 and SF1 represent multilineage PitNETs. These rare tumors have variable clinical and morphological features, most often presenting as large tumors with GH excess and occasionally as one of multiple synchronous PitNETs of distinct lineages., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To investigate the incidence of corticotroph hyperplasia (CH) or lymphocyte infiltration in the pituitary of patients with obesity., Methods: The pituitary and adrenal glands from 161 adult autopsies performed between 2010 and 2019 at our institution were reviewed. The clinical history, body mass index (BMI), and cause of death were recorded. Routine hematoxylin and eosin staining, reticulin staining, and immunohistochemical staining for adrenocorticotropic hormone, CD3, and CD20 were performed. The results were analyzed using the Fisher and chi-square statistics. Decedents were separated into 4 groups based on BMI (kg/m 2 ): (1) lean (BMI, <25.0), (2) overweight (BMI, 25.0-29.9), (3) obesity class I (BMI, 30.0-34.9), and (4) obesity classes II to III (BMI, >34.9)., Results: CH/neoplasia was identified in 44 of 161 pituitary glands. Four (9.1%) of 53 lean patients had pituitary lesions, whereas 27.3% (12) of overweight, 22.7% (10) of obesity class I, and 40.9% (18) of obesity class II patients had hyperplasia (P < .0001). Small corticotroph tumors were identified in 15 patients; only 1 was a lean patient, and the tumor was associated with the Crooke hyaline change of nontumorous corticotrophs. The presence of CH and neoplasia was associated with adrenal cortical hyperplasia and lipid depletion. Microscopic foci of T and B lymphocytes were identified in the pituitaries of patients in each weight category; no independent association between BMI and lymphocyte inflammation was found., Conclusion: Our data indicate an association between CH/neoplasia and obesity. It remains unclear whether obesity is the cause or effect of adrenocorticotropic hormone and cortisol excess., Competing Interests: Disclosure The authors have no multiplicity of interest to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Treatment with radiolabelled somatostatin analogs, a form of peptide receptor radionuclide therapy (PRRT), has changed the management of patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). There is a subgroup of patients who have suboptimal benefit and rapidly progress on PRRT, indicating that accurate prognostic and predictive markers are urgently needed. Currently, most of the literature concentrate on the prognostic impact of the dual positron emission tomography (PET) scan with very few information regarding the predictive value. We report a case series and review the literature to summarizes the predictive value of combined somatostatin receptor (SSTR) and fluorodeoxyglucose (FDG) PET in metastatic GEP-NETs. We conducted a review of the literature for data published from 2010 to 2021 in MEDLINE, Embase, the National Institutes of Health trial registry, Cochrane CENTRAL, and published proceedings from major gastrointestinal and neuroendocrine cancer meetings. Our main criteria included all published prospective and retrospective data in which the predictive value of dual PET scans using SSTR and FDG was correlated with PRRT response in patients with metastatic GEP-NETs. We summarized clinical outcomes including progression-free survival (PFS), overall survival (OS), and post-therapy complications associated with PRRT according to FDG avidity. We excluded studies that did not include FDG PET scan, GEP patients, studies with no clear predictive value of the FDG PET scan, and studies that did not report a direct correlation between FDG avidity and primary outcome. Additionally, we summarized our institutional experience in eight patients who progressed during or within the first year of PRRT treatment. Our search identified 1306 articles; most of them showed only the prognostic value of Integrated SSTR/FDG PET imaging biomarker in GEP-NETs. Only three studies (n=75 patients) met our inclusion criteria and retrospectively investigated the predictive value of dual SSTR and FDG imaging in subjects being considered for PRRT. The results confirmed that FDG avidity correlates with advanced NET grades. Lesions that are both SSTR and FDG avid had early disease progression. In one study, at multivariate analysis, FDG PET results were independently predictive of lower PFS for PRRT. In our case series, there were eight patients with metastatic well-differentiated GEP-NETs (grades 2 and 3) who progressed within one year of PRRT. Seven of them had positive FDG PET scan at the time of progression. In conclusion, Dual SSTR/FDG PET imaging has a potential predictive impact for PRRT in GEP-NETs. It permits the capturing of the disease complexity and aggressiveness, which correlates with PRRT response. Therefore, prospective future trials should validate the predictive value of dual SSTRs/FDG PET for better PRRT stratification., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-1011/coif). The authors have no conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.)

The tumor formerly known as "cauda equina paraganglioma" was recently renamed as cauda equina neuroendocrine tumor (CENET) based on distinct biological and genetic properties. Nevertheless, it remains insufficiently understood. For this study, we retrieved CENETs (some previously reported), from the pathology files of 3 institutions; we examined their immunohistochemical profile, including common neuroendocrine tumor-associated hormones and transcription factors. We identified 24 CENETs from 7 female and 17 male adult patients, with a median age of 47 years. Six included neurofilament-positive ganglion cells. All tumors tested were positive for INSM1, synaptophysin, chromogranin A, SSTR2, and CD56 as well as at least 1 keratin (AE1/AE3, CAM5.2); CK7 and CK20 were negative. Glial fibrillary acidic protein was negative, except for peripheral nontumoral elements. S100 protein was variable but mainly expressed in scattered sustentacular cells. All but 1 tumor tested were positive for HOXB13; several stained for SATB2, and all tumors were consistently negative for GATA3. All tumors tested were negative for transcription factors found in various other epithelial neuroendocrine neoplasms including TTF1, CDX2, PIT1, TPIT, SF1, and PAX8; staining for T-brachyury was negative. Four of 5 CENETs tested had at least focal tyrosine hydroxylase reactivity. Serotonin expression was detected in all 21 tumors tested; it was diffusely positive in 5 and had variable positivity in the remainder. A few tumors had scattered cells expressing gastrin, calcitonin, pancreatic polypeptide, and peptide YY, while glucagon, adrenocorticotropic hormone, and monoclonal carcinoembryonic antigen were negative. PSAP expression was found focally in 4 of 5 tumors examined. SDHB was consistently intact; ATRX was intact in 14 tumors and showed only focal loss in 3. The median Ki-67 labeling index was 4.5% (range: 1% to 15%). We conclude that CENET represents a distinct neuroendocrine neoplasm; the subset with ganglion cells qualifies for designation as composite gangliocytoma/neuroma-neuroendocrine tumor (CoGNET) as defined in the 2022 WHO classification of neuroendocrine neoplasms. In addition to INSM1, chromogranin, synaptophysin, and keratins, the most characteristic finding is nuclear HOXB13 expression; a subset also express SATB2. Serotonin is the most common hormone expressed. The cytogenesis and pathogenesis of these lesions remains unclear., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Appendiceal neuroendocrine neoplasms (ANENs) usually present as incidental findings at the time of appendectomy for acute appendicitis. They are rare, accounting for only 0.5-1% of intestinal neoplasms; they are found in 0.3-0.9% of all appendectomy specimens. They are usually sporadic tumors. There are several histological types including well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Histologic differentiation and the grade of well-differentiated NETs correlate with clinical behavior and prognosis. Management varies based on differentiation, aggressiveness, and metastatic potential. There is debate about the optimal surgical management for localized appendiceal NETs that are impacted by many factors including the tumor size, the extent of mesoappendiceal spread, lymphovascular invasion and perineural involvement. In addition, the data to guide therapy in metastatic disease are limited due to the paucity of these tumors. Here, we review the current advances in the management of ANENs within the context of a multidisciplinary approach to these tumors.

Ameloblastoma is a benign, locally aggressive odontogenic neoplasm with variable solid and cystic morphology. On account of its histologic variety, diagnostically challenging cases can bear resemblance to odontogenic keratocyst/keratocystic odontogenic tumor (KCOT) or dentigerous cyst (DC). BRAF V600E mutation has been reported to be specific for and frequent in ameloblastoma, and this study evaluated the usefulness of immunohistochemistry (IHC) using the BRAF VE1 mutant-specific antibody as a diagnostic adjunct in this setting. We investigated 46 ameloblastomas, 30 KCOTs, and 30 DCs. BRAF VE1 IHC was performed on all cases and allele-specific polymerase chain reaction (AS-PCR) for BRAF V600E mutation was performed on 30 ameloblastomas and any IHC-positive KCOT/DC. BRAF VE1 IHC was positive in 31/37 (83.8%) mandibular ameloblastomas but not in any maxillary ameloblastomas (0/9), KCOT (0/30), or DC (0/30). Equivocal staining was seen in 1/37 (3.3%) mandibular ameloblastomas. Of the 30 ameloblastomas subjected to AS-PCR, BRAF V600E mutation was identified in 19/23 (82.6%) mandibular ameloblastomas and 0/7 (0.0%) maxillary ameloblastomas. BRAF V600E mutant ameloblastomas were positive by IHC in 18/19 (94.7%) cases and equivocal in 1/19 (5.3%) cases. All 11 (100.0%) BRAF-wild type ameloblastomas were negative by IHC. BRAF VE1 is an excellent tool for the diagnosis of mandibular ameloblastoma but of limited utility in the maxilla, where it less commonly occurs and where BRAF V600E mutation is considerably less frequent., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Importance: Adrenalectomy is the definitive treatment for multiple adrenal abnormalities. Advances in technology and genomics and an improved understanding of adrenal pathophysiology have altered operative techniques and indications., Objective: To develop evidence-based recommendations to enhance the appropriate, safe, and effective approaches to adrenalectomy., Evidence Review: A multidisciplinary panel identified and investigated 7 categories of relevant clinical concern to practicing surgeons. Questions were structured in the framework Population, Intervention/Exposure, Comparison, and Outcome, and a guided review of medical literature from PubMed and/or Embase from 1980 to 2021 was performed. Recommendations were developed using Grading of Recommendations, Assessment, Development and Evaluation methodology and were discussed until consensus, and patient advocacy representation was included., Findings: Patients with an adrenal incidentaloma 1 cm or larger should undergo biochemical testing and further imaging characterization. Adrenal protocol computed tomography (CT) should be used to stratify malignancy risk and concern for pheochromocytoma. Routine scheduled follow-up of a nonfunctional adrenal nodule with benign imaging characteristics and unenhanced CT with Hounsfield units less than 10 is not suggested. When unilateral disease is present, laparoscopic adrenalectomy is recommended for patients with primary aldosteronism or autonomous cortisol secretion. Patients with clinical and radiographic findings consistent with adrenocortical carcinoma should be treated at high-volume multidisciplinary centers to optimize outcomes, including, when possible, a complete R0 resection without tumor disruption, which may require en bloc radical resection. Selective or nonselective α blockade can be used to safely prepare patients for surgical resection of paraganglioma/pheochromocytoma. Empirical perioperative glucocorticoid replacement therapy is indicated for patients with overt Cushing syndrome, but for patients with mild autonomous cortisol secretion, postoperative day 1 morning cortisol or cosyntropin stimulation testing can be used to determine the need for glucocorticoid replacement therapy. When patient and tumor variables are appropriate, we recommend minimally invasive adrenalectomy over open adrenalectomy because of improved perioperative morbidity. Minimally invasive adrenalectomy can be achieved either via a retroperitoneal or transperitoneal approach depending on surgeon expertise, as well as tumor and patient characteristics., Conclusions and Relevance: Twenty-six clinically relevant and evidence-based recommendations are provided to assist surgeons with perioperative adrenal care.

Ki-67 assessment is a key step in the diagnosis of neuroendocrine neoplasms (NENs) from all anatomic locations. Several challenges exist related to quantifying the Ki-67 proliferation index due to lack of method standardization and inter-reader variability. The application of digital pathology coupled with machine learning has been shown to be highly accurate and reproducible for the evaluation of Ki-67 in NENs. We systematically reviewed all published studies on the subject of Ki-67 assessment in pancreatic NENs (PanNENs) employing digital image analysis (DIA). The most common advantages of DIA were improvement in the standardization and reliability of Ki-67 evaluation, as well as its speed and practicality, compared to the current gold standard approach of manual counts from captured images, which is cumbersome and time consuming. The main limitations were attributed to higher costs, lack of widespread availability (as of yet), operator qualification and training issues (if it is not done by pathologists), and most importantly, the drawback of image algorithms counting contaminating non-neoplastic cells and other signals like hemosiderin. However, solutions are rapidly developing for all of these challenging issues. A comparative meta-analysis for DIA versus manual counting shows very high concordance (global coefficient of concordance: 0.94, 95% CI: 0.83-0.98) between these two modalities. These findings support the widespread adoption of validated DIA methods for Ki-67 assessment in PanNENs, provided that measures are in place to ensure counting of only tumor cells either by software modifications or education of non-pathologist operators, as well as selection of standard regions of interest for analysis. NENs, being cellular and monotonous neoplasms, are naturally more amenable to Ki-67 assessment. However, lessons of this review may be applicable to other neoplasms where proliferation activity has become an integral part of theranostic evaluation including breast, brain, and hematolymphoid neoplasms., (© 2022. The Author(s).)

Gut microbiome balance plays a key role in human health and maintains gut barrier integrity. Dysbiosis, referring to impaired gut microbiome, is linked to a variety of diseases, including cancers, through modulation of the inflammatory process. Most studies concentrated on adenocarcinoma of different sites with very limited information on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we have analyzed the gut microbiome (both fungal and bacterial communities) in patients with metastatic GEP-NENs. Fecal samples were collected and compared with matched healthy control samples using logistic regression distances utilizing R package MatchIt (version 4.2.0, Daniel E. Ho, Stanford, CA, USA). We examined differences in microbiome profiles between GEP-NENs and control samples using small subunit (SSU) rRNA (16S), ITS1, ITS4 genomic regions for their ability to accurately characterize bacterial and fungal communities. We correlated the results with different behavioral and dietary habits, and tumor features including differentiation, grade, primary site, and therapeutic response. All tests are two-sided and p -values ≤ 0.05 were considered statistically significant. Gut samples of 34 patients (12 males, 22 females, median age 64 years) with metastatic GEP-NENs (22 small bowel, 10 pancreatic, 1 gall bladder, and 1 unknown primary) were analyzed. Twenty-nine patients had well differentiated GEP-neuroendocrine tumors (GEP-NETs), (G1 = 14, G2 = 12, G3 = 3) and five patients had poorly differentiated GEP-neuroendocrine carcinomas (GEP-NECs). Patients with GEP-NENs had significantly decreased bacterial species and increased fungi (notably Candida species, Ascomycota, and species belonging to saccharomycetes) compared to controls. Patients with GEP-NECs had significantly enriched populations of specific bacteria and fungi (such as Enterobacter hormaechei , Bacteroides fragilis and Trichosporon asahii ) compared to those with GEP-NETs ( p = 0.048, 0.0022 and 0.034, respectively). In addition, higher grade GEP-NETs were associated with significantly higher Bacteroides fragilis ( p = 0.022), and Eggerthella lenta ( p = 0.00018) species compared to lower grade tumors. There were substantial differences associated with dietary habits and therapeutic responses. This is the first study to analyze the role of the microbiome environment in patients with GEP-NENs. There were significant differences between GEP-NETs and GEP-NECs, supporting the role of the gut microbiome in the pathogenesis of these two distinct entities.

Background: Multinodular goiter (MNG) is the most common disorder of the thyroid gland. Aging and genetic mutations that impair thyroid hormone (TH) production have been implicated in the development of MNG. XB130 is an adaptor/scaffold protein predominantly expressed in the thyroid gland. XB130 deficiency leads to transient postnatal growth retardation in mice due to congenital hypothyroidism. We studied the formation of MNG and possible mechanisms in elderly mice. Methods: Thyroid glands of male and female Xb130- knockout ( Xb130 -/- ), heterozygous ( Xb130 +/- ), and wild-type ( Xb130 +/+ ) mice at the ages of 12-20 months were harvested for visual examination, histopathological, and immunohistological analyses. Blood and thyroid samples were collected after feeding elderly mice with a low iodine diet for 125 I uptake and perchlorate discharge assay. The activity of thyroperoxidase (Tpo) was examined by spectrophotometric evaluation of iodide oxidation. Results: While moderate MNG was seen in Xb130 +/+ and Xb130 +/- mice, severe MNG, characterized by multiple nodules intermixed with dilated colloid-rich macrofollicles, was found only in Xb130 -/- mice at 18 months. Thyrocyte cytoskeletal structure and cell adhesion molecules were disorganized, and TH production was significantly reduced. Reduced iodide organification was seen in elderly Xb130 +/+ mice and further enhanced in Xb130 -/- mice. In Xb130 +/+ mice, Tpo shows high affinity with hydrogen peroxide (H 2 O 2 ) throughout aging, but reduced affinity with iodide in an age-dependent manner. By contrast, in elderly Xb130 -/- mice, the affinity of Tpo for iodide remained high, but the affinity of Tpo for H 2 O 2 was reduced. Conclusions: The pathophysiological features in the thyroid glands of aged Xb130 -/- mice closely resemble the features of MNG in humans. Moderate MNG in elderly mice was dramatically aggravated by XB130 deficiency. Reduced affinity of Tpo for H 2 O 2 may contribute to MNG development via oxidative stress. This could be specific to XB130 deficiency but also could be a common mechanism in MNG. Its clinical relevance should be further investigated.

The entity known as pituitary carcinoma has been traditionally defined as a tumor of adenohypophysial cells that metastasizes systemically or craniospinally independent of the histological appearance of the lesion. Reported cases of pituitary carcinoma have clinically and histologically resembled their non-metastatic counterparts that were classified as adenomas; the majority of cases were initially diagnosed as adenomas, and with tumor progression and spread, the diagnosis was changed to carcinoma. This classification has been challenged since the definition of malignancy in most organs is not based only on metastatic spread. The extent of local invasion resulting in an inability to completely resect an adenohypophysial tumor can have serious consequences that can cause harm and are therefore not benign. To address this dilemma, it was proposed that pituitary tumors be classified as neuroendocrine tumors. This change in nomenclature is totally appropriate since these tumors are composed of classical neuroendocrine cells; as with other neuroendocrine tumors, they have variable behavior that can be indolent but can involve metastasis. With the new nomenclature, there is no requirement for a distinction between adenomas and carcinomas. Moreover, the WHO/IARC has provided an overarching classification for neuroendocrine neoplasms at all body sites; in this new classification, the term 'neuroendocrine carcinoma' is reserved for poorly differentiated high-grade malignancies that are clinically, morphologically and genetically distinct from well-differentiated neuroendocrine tumors. It remains to be determined if there are true pituitary neuroendocrine carcinomas., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review., (© The authors.)

This review summarizes the changes in the 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors that relate to the thyroid gland. The new classification has divided thyroid tumors into several new categories that allow for a clearer understanding of the cell of origin, pathologic features (cytopathology and histopathology), molecular classification, and biological behavior. Follicular cell-derived tumors constitute the majority of thyroid neoplasms. In this new classification, they are divided into benign, low-risk, and malignant neoplasms. Benign tumors include not only follicular adenoma but also variants of adenoma that are of diagnostic and clinical significance, including the ones with papillary architecture, which are often hyperfunctional and oncocytic adenomas. For the first time, there is a detailed account of the multifocal hyperplastic/neoplastic lesions that commonly occur in the clinical setting of multinodular goiter; the term thyroid follicular nodular disease (FND) achieved consensus as the best to describe this enigmatic entity. Low-risk follicular cell-derived neoplasms include non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), thyroid tumors of uncertain malignant potential, and hyalinizing trabecular tumor. Malignant follicular cell-derived neoplasms are stratified based on molecular profiles and aggressiveness. Papillary thyroid carcinomas (PTCs), with many morphological subtypes, represent the BRAF-like malignancies, whereas invasive encapsulated follicular variant PTC and follicular thyroid carcinoma represent the RAS-like malignancies. This new classification requires detailed subtyping of papillary microcarcinomas similar to their counterparts that exceed 1.0 cm and recommends not designating them as a subtype of PTC. The criteria of the tall cell subtype of PTC have been revisited. Cribriform-morular thyroid carcinoma is no longer classified as a subtype of PTC. The term "Hürthle cell" is discouraged, since it is a misnomer. Oncocytic carcinoma is discussed as a distinct entity with the clear recognition that it refers to oncocytic follicular cell-derived neoplasms (composed of > 75% oncocytic cells) that lack characteristic nuclear features of PTC (those would be oncocytic PTCs) and high-grade features (necrosis and ≥ 5 mitoses per 2 mm 2 ). High-grade follicular cell-derived malignancies now include both the traditional poorly differentiated carcinoma as well as high-grade differentiated thyroid carcinomas, since both are characterized by increased mitotic activity and tumor necrosis without anaplastic histology and clinically behave in a similar manner. Anaplastic thyroid carcinoma remains the most undifferentiated form; squamous cell carcinoma of the thyroid is now considered as a subtype of anaplastic carcinoma. Medullary thyroid carcinomas derived from thyroid C cells retain their distinct section, and there is a separate section for mixed tumors composed of both C cells and any follicular cell-derived malignancy. A grading system for medullary thyroid carcinomas is also introduced based on mitotic count, tumor necrosis, and Ki67 labeling index. A number of unusual neoplasms that occur in the thyroid have been placed into new sections based on their cytogenesis. Mucoepidermoid carcinoma and secretory carcinoma of the salivary gland type are now included in one section classified as "salivary gland-type carcinomas of the thyroid." Thymomas, thymic carcinomas and spindle epithelial tumor with thymus-like elements are classified as "thymic tumors within the thyroid." There remain several tumors whose cell lineage is unclear, and they are listed as such; these include sclerosing mucoepidermoid carcinoma with eosinophilia and cribriform-morular thyroid carcinoma. Another important addition is thyroblastoma, an unusual embryonal tumor associated with DICER1 mutations. As in all the WHO books in the 5th edition, mesenchymal and stromal tumors, hematolymphoid neoplasms, germ cell tumors, and metastatic malignancies are discussed separately. The current classification also emphasizes the value of biomarkers that may aid diagnosis and provide prognostic information., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)