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Frontiers in Endocrinology 2021Hürthle cell lesions have been a diagnostic conundrum in pathology since they were first recognized over a century ago. Controversy as to the name of the cell, the... (Review)
Review
Hürthle cell lesions have been a diagnostic conundrum in pathology since they were first recognized over a century ago. Controversy as to the name of the cell, the origin of the cell, and even which cells in particular may be designated as such still challenge pathologists and confound those treating patients with a diagnosis of "Hürthle cell" anything within the diagnosis, especially if that anything is a sizable mass lesion. The diagnosis of Hürthle cell adenoma (HCA) or Hürthle cell carcinoma (HCC) has typically relied on a judgement call by pathologists as to the presence or absence of capsular and/or vascular invasion of the adjacent thyroid parenchyma, easy to note in widely invasive disease and a somewhat subjective diagnosis for minimally invasive or borderline invasive disease. Diagnostic specificity, which has incorporated a sharp increase in molecular genetic studies of thyroid tumor subtypes and the integration of molecular testing into preoperative management protocols, continues to be challenged by Hürthle cell neoplasia. Here, we provide the improving yet still murky state of what is known about Hürthle cell tumor genetics, clinical management, and based upon what we are learning about the genetics of other thyroid tumors, how to manage expectations, by pathologists, clinicians, and patients, for more actionable, precise classifications of Hürthle cell tumors of the thyroid.
Topics: Adenoma, Oxyphilic; Biopsy; Genome, Mitochondrial; Humans; Mutation; Oxyphil Cells; Thyroid Neoplasms; Thyroidectomy
PubMed: 34177816
DOI: 10.3389/fendo.2021.696386 -
Frontiers in Endocrinology 2021Familial non-medullary thyroid carcinoma (FNMTC) corresponds to 5-10% of all follicular cell-derived carcinoma (FCDTC). Oncocytic thyroid tumors have an increased... (Review)
Review
Familial non-medullary thyroid carcinoma (FNMTC) corresponds to 5-10% of all follicular cell-derived carcinoma (FCDTC). Oncocytic thyroid tumors have an increased incidence in the familial context in comparison with sporadic FCDTC, encompassing benign and malignant tumors in the same family presenting with some extent of cell oxyphilia. This has triggered the interest of our and other groups to clarify the oncocytic change, looking for genetic markers that could explain the emergence of this phenotype in thyroid benign and malignant lesions, focusing on familial aggregation. Despite some advances regarding the identification of the gene associated with retinoic and interferon-induced mortality 19 (GRIM-19), as one of the key candidate genes affected in the "Tumor with Cell Oxyphilia" (TCO) locus, most of the mutations follow a pattern of "private mutations", almost exclusive to one family. Moreover, no causative genetic alterations were identified so far in most families. The incomplete penetrance of the disease, the diverse benign and malignant phenotypes in the affected familial members and the variable syndromic associations create an additional layer of complexity for studying the genetic alterations in oncocytic tumors. In the present review, we summarized the available evidence supporting genomic-based mechanisms for the oncocytic change, particularly in the context of FNMTC. We have also addressed the challenges and gaps in the aforementioned mechanisms, as well as molecular clues that can explain, at least partially, the phenotype of oncocytic tumors and the respective clinico-pathological behavior. Finally, we pointed to areas of further investigation in the field of oncocytic (F)NMTC with translational potential in terms of therapy.
Topics: Animals; Genetic Predisposition to Disease; Genome, Mitochondrial; Humans; Mutation; Oxyphil Cells; Thyroid Neoplasms
PubMed: 34177813
DOI: 10.3389/fendo.2021.691979 -
Frontiers in Endocrinology 2021Oncocytes are cells that have abundant eosinophilic cytoplasm due to the accumulation of mitochondria; they are also known as oxyphils. In the thyroid they have been... (Review)
Review
Oncocytes are cells that have abundant eosinophilic cytoplasm due to the accumulation of mitochondria; they are also known as oxyphils. In the thyroid they have been called Hürthle cells but this is a misnomer, since Hürthle described C cells; for this reason, we propose the use of "oncocyte" as a scientific term rather than an incorrect eponym. Oncocytic change occurs in nontumorous thyroid disorders, in benign and malignant tumors of thyroid follicular cells, in tumors composed of thyroid C cells, and intrathyroidal parathyroid proliferations as well as in metastatic lesions. The morphology of primary oncocytic thyroid tumors is similar to that of their non-oncocytic counterparts but also is complicated by the cytologic features of these cells that include both abundant eosinophilic cytoplasm and large cherry red nucleoli. The molecular alterations in oncocytic thyroid tumors echo those of their non-oncocytic counterparts but in addition feature mitochondrial DNA mutations as well as chromosomal gains and losses. In this review we emphasize the importance of recognition of the spectrum of oncocytic thyroid pathology. The cell of origin, morphologic features including architecture, nuclear atypia and invasive growth, as well as high grade features such as mitoses and necrosis, enable accurate classification of these lesions. The molecular alterations underlying the pathological entity are associated with genetic alterations associated with oncocytic change. The arbitrary cut-off of 75% oncocytic change to classify a lesion as an oncocytic variant brings another complexity to the classification scheme of tumors that frequently have mixed oncocytic and non-oncocytic components. This controversial and often confusing area of thyroid pathology requires thoughtful and cautious investigation to clarify accurate diagnosis, prognosis and prediction for patients with oncocytic thyroid lesions.
Topics: Adenoma, Oxyphilic; Humans; Oxyphil Cells; Thyroid Gland; Thyroid Neoplasms
PubMed: 34012422
DOI: 10.3389/fendo.2021.678119 -
Thyroid : Official Journal of the... Mar 2022Follicular thyroid carcinoma (FTC) and Hurthle cell carcinoma (HCC) are rare and aggressive thyroid cancers with limited published data comparing their outcomes or...
Follicular thyroid carcinoma (FTC) and Hurthle cell carcinoma (HCC) are rare and aggressive thyroid cancers with limited published data comparing their outcomes or regarding their subtypes. The aim of this study was to describe clinicopathological features and compare clinical outcomes of patients with FTC and HCC based on the 2017 World Health Organization definition and extent of vascular invasion (VI). We retrospectively studied 190 patients with HCC and FTC primarily treated with surgery at Memorial Sloan Kettering Cancer Center between 1986 and 2015. Patients were classified as minimally invasive (MI), encapsulated angioinvasive with focal VI (EA-FVI), encapsulated angioinvasive with extensive VI (EA-EVI), and as widely invasive (WI). To compare clinical outcomes, patients were grouped as follows: group 1 = FTC-MI and FTC EA-FVI, group 2 = FTC EA-EVI and FTC-WI, group 3 = HCC-MI and HCC EA-FVI, group 4 = HCC EA-EVI and HCC-WI. Outcomes of interest were overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS), and distant recurrence-free survival (DRFS). Outcomes were determined using the Kaplan-Meier method and compared with log-rank test. Patients with HCC ( = 111) were more likely to be older than 55 years old (59% vs. 27%, < 0.001) with a tendency to present with more extensive VI (33% vs. 19%, = 0.07) compared with FTC ( = 79). Comparing groups 1, 2, 3, and 4, group 4 patients were more likely to recur (DFS 98%, 93%, 98% vs. 73%, respectively, = 0.0069). There was no statistically significant difference in OS, DSS LRRFS, or DRFS. Stratified by extent of VI (no, focal, and extensive VI), patients with extensive VI were more likely to recur (RFS 100%, 95%, 77%, = 0.0025) and had poorer distant control (DRFS: 100%, 95%, 80%, = 0.022), compared with patients absent or focal VI. Accurate assessment of the extent of VI and tumor phenotype (follicular vs. Hurthle) are essential in identifying patients at higher risk of recurrence.
Topics: Adenocarcinoma, Follicular; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Oxyphil Cells; Prognosis; Retrospective Studies; Thyroid Neoplasms
PubMed: 35078345
DOI: 10.1089/thy.2021.0424 -
Cancer Discovery Aug 2023Oncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here,...
UNLABELLED
Oncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA sequencing and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against lipid peroxides and ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity.
SIGNIFICANCE
HCC harbors abundant mitochondria, mitochondrial DNA mutations, and chromosomal losses. Using a CRISPR-Cas9 screen inspired by transcriptomic and metabolomic profiling, we identify molecular effectors essential for cell fitness. We uncover lipid peroxide stress as a vulnerability coupled to mitochondrial complex I loss in HCC. See related article by Frank et al., p. 1884. This article is highlighted in the In This Issue feature, p. 1749.
Topics: Humans; Thyroid Gland; Carcinoma, Hepatocellular; Lipid Peroxides; Fermentation; Oxyphil Cells; Liver Neoplasms; DNA, Mitochondrial
PubMed: 37262067
DOI: 10.1158/2159-8290.CD-22-0976 -
Head and Neck Pathology Mar 2023Oncocytes are a component of many metaplastic and neoplastic lesions throughout the head and neck area, primarily originating in salivary/seromucinous glands and the... (Review)
Review
BACKGROUND
Oncocytes are a component of many metaplastic and neoplastic lesions throughout the head and neck area, primarily originating in salivary/seromucinous glands and the thyroid gland. In addition, other lesions can contain cells that mimic oncocytes (pseudo-oncocytes); these can be of epithelial or non-epithelial origin.
METHODS
Review article.
RESULTS
Oncocytic metaplasia is common in seromucinous glands throughout the upper aerodigestive tract, most notable in the oral cavity, nasopharynx and larynx. The main oncocytic salivary gland neoplasms are Warthin tumor and oncocytoma. Infarction of Warthin tumor may lead to recognition difficulties. Oncocytic subtypes of mucoepidermoid carcinoma and intraductal carcinoma have morphologic and immunohistochemical features that allow distinction from major oncocytic entities. Oncocytic thyroid tumors include adenoma, carcinoma (follicular, papillary and medullary), along with poorly differentiated tumors. Oncocytic papillary sinonasal and middle ear tumors must be distinguished from low grade adenocarcinomas. Pseudo-oncocytic entities include paraganglioma, Langerhans cell histiocytosis, giant cell tumor, rhabdomyoma, and metastatic tumors.
CONCLUSIONS
Correct diagnosis of oncocytic head and neck lesions requires a knowledge of the spectrum of possible entities, their characteristic sites of occurrence, architecture, histomorphology, and immunohistochemistry. Oncocytic subtypes of several newly described entities are now recognized. Both epithelial and non-epithelial mimics of oncocytes exist. The molecular features of oncocytic tumors can be helpful in their diagnosis and understanding their pathogenesis.
Topics: Humans; Oxyphil Cells; Adenolymphoma; Salivary Gland Neoplasms; Salivary Glands; Adenoma, Oxyphilic
PubMed: 36928735
DOI: 10.1007/s12105-022-01520-y -
Frontiers in Endocrinology 2021In fine-needle aspirations (FNA) of thyroid, Hürthle cells can be found in a broad spectrum of lesions, ranging from non-neoplastic conditions to aggressive malignant... (Review)
Review
In fine-needle aspirations (FNA) of thyroid, Hürthle cells can be found in a broad spectrum of lesions, ranging from non-neoplastic conditions to aggressive malignant tumors. Recognize them morphologically, frequently represents a challenging for an adequately diagnosis and are associated with a significant interobserver variability. Although the limitations of the morphologic diagnosis still exist, the interpretation of the context where the cells appear and the recent advances in the molecular knowledge of Hürthle cells tumors are contributing for a more precise diagnosis. This review aims to describe the cytology aspects of all Hürthle cells neoplastic and non-neoplastic thyroid lesions, focusing on the differential diagnosis and reporting according to The Bethesda System for Reporting Thyroid Cytology (TBSRTC). New entities according to the latest World Health Organization (WHO) classification are included, as well as an update of the current molecular data.
Topics: Biopsy, Fine-Needle; Cytodiagnosis; Diagnosis, Differential; Humans; Oxyphil Cells; Thyroid Gland; Thyroid Neoplasms; Thyroid Nodule
PubMed: 34248855
DOI: 10.3389/fendo.2021.701877 -
Cancer Research Communications Jul 2023Hürthle cell carcinoma (HCC) is a rare type of thyroid cancer with high rates of distant metastasis and recurrence. Along with the scarcity of effective systemic...
UNLABELLED
Hürthle cell carcinoma (HCC) is a rare type of thyroid cancer with high rates of distant metastasis and recurrence. Along with the scarcity of effective systemic therapies for HCC, these factors contribute to poor clinical outcomes. The immunologic features of HCC are poorly defined and response rates with immune checkpoint blockade have not been reported. A more comprehensive understanding of the immune landscape and factors that predict response to checkpoint inhibitors is needed. We performed RNA sequencing on 40 tumors to characterize the neoantigen landscape and immune microenvironment of HCC. We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T-cell activation/dysfunction and correlated these to genetic features such as tumor mutation burden, neoantigen burden, mitochondrial mutations, and LOH from chromosomal uniparental disomy. Finally, immune profiles of patients with recurrence were compared with those of patients without recurrence. HCC tumors exhibited low levels of immune infiltration, with the more aggressive widely invasive phenotype associated with more immune depletion. There was a negative correlation between tumor mutation burden, neoantigen burden, programmed cell death ligand 1 (PD-L1) expression, and the immune infiltration score. HCC tumors that exhibited a global LOH from chromosomal uniparental disomy or haploidization had the lowest level of immune infiltration. HCC tumors that recurred displayed an immune-depleted microenvironment associated with global LOH and aerobic glycolysis. These findings offer new insights into the functional immune landscapes and immune microenvironment of HCC. Our data identify potential immunologic vulnerabilities for these understudied and often fatal cancers.
SIGNIFICANCE
The immune landscape of HCC is poorly defined and response rates to immunotherapy have not been reported. The authors found the immune microenvironment in HCC to be depleted. This immunosuppression is associated with a global LOH from haploidization and uniparental disomy, resulting in whole chromosome losses across the genome.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Uniparental Disomy; Oxyphil Cells; B7-H1 Antigen; Tumor Microenvironment
PubMed: 37529400
DOI: 10.1158/2767-9764.CRC-23-0120 -
Cancer Cytopathology May 2021
Topics: Humans; Oxyphil Cells; Thyroid Neoplasms
PubMed: 33045148
DOI: 10.1002/cncy.22377