Psammomatous calcifications in thyroid oncocytic (Hürthle cell) follicular tumors.

Concentric calcifications, also known as psammoma bodies, are a relatively frequent finding in certain types of tumors, particularly papillary thyroid carcinoma (PTC). In the thyroid, they have been assigned a significant role in the diagnosis of PTC and in distinguishing between these tumors and other types of thyroid neoplasms. Concentric calcifications have also less commonly been noted in other processes in the thyroid, such as in tumors characterized by cells containing abundant oxyphilic cytoplasm (i.e., Hürthle cells). We have studied 12 patients with oncocytic thyroid follicular tumors that contained scattered psammomatous calcifications that led to difficulties in diagnosis. The patients were 9 women and 3 men, aged 34 to 63 years. 10 cases corresponded to benign, non-invasive oncocytic tumors and 2 cases were minimally invasive follicular carcinomas of oncocytic (so called Hürthle cell) type. The psammomatous calcifications were randomly scattered throughout the lesions and were present as a focal, incidental finding in 8 cases and were diffuse in 4 cases. They were composed of concentrically laminated deposits of dense basophilic material closely resembling psammoma bodies, often associated with more homogeneous deposits of lightly eosinophilic material without concentric lamination that were interpreted as precipitated thyroglobulin. Seven patients with clinical follow-up, including one with minimally invasive carcinoma, were alive and well between 5 and 12 years after diagnosis. Concentric laminated calcifications may be encountered in oncocytic (Hürthle cell) follicular tumors and should not be interpreted as indicative of PTC in the context of oncocytic neoplasms of the thyroid.

Integrated transcriptomic and proteomic analyses for the characterization of parathyroid oxyphil cells in uremic patients.

Chief cells are the predominant cells in parathyroid glands of healthy adults; however, parathyroid oxyphil cells, whose function is unknown, increase dramatically in patients with secondary hyperparathyroidism (SHPT). Calcitriol and calcimimetics are the most powerful treatments for SHPT, while the mechanisms leading to calcitriol or calcimimetic resistance in oxyphil cell-predominant SHPT are unknown. Here we used transcriptomic and proteomic techniques to characterize oxyphil cells by comparing the differences between chief and oxyphil cell nodules of parathyroid glands in uremic patients. Compared to chief cell nodules, the most marked expression increases in oxyphil cell nodules were for mitochondrion-associated proteins. The mitochondria number and mitochondrial DNA content were also significantly increased in oxyphil cell nodules. Moreover, oxyphil cell nodules expressed parathyroid-specific factors, and exhibited lower levels of proliferation-related proteins but higher synthesis and secretion level of parathyroid hormone (PTH). The protein expression of SHPT-regulating factors, including vitamin-D receptor, calcium-sensing receptor and Klotho, were significantly downregulated in oxyphil cell nodules. Therefore, oxyphil cells characterized by enrich mitochondria in uremic patients showed higher synthesis and secretion of PTH but lower expression of SHPT regulators than chief cells, which may contribute to the pathophysiology of SHPT and the treatment resistance to calcitriol and calcimimetics.

Renal cell carcinomas with tubulopapillary architecture and oncocytic cells: Molecular analysis of 39 difficult tumors to classify.

So-called oncocytic papillary renal cell carcinoma (OPRCC) is a poorly defined variant of papillary renal cell carcinoma. Since its first description, several studies were published with conflicting results, and thus precise definition is lacking. A cohort of 39 PRCCs composed of oncocytic cells were analyzed. Cases were divided into 3 groups based on copy number variation (CNV) pattern. The first group consisted of 23 cases with CNV equal to renal oncocytoma. The second group consisted of 7 cases with polysomy of chromosomes 7 and 17 and the last group of 9 cases included those with variable CNV. Epidemiologic, morphologic and immunohistochemical features varied among the groups. There were not any particular histomorphologic features correlating with any of the genetic subgroups. Further, a combination of morphologic, immunohistochemical, and molecular-genetic features did not allow to precisely predict biologic behavior. Owing to variable CNV pattern in OPRCC, strict adherence to morphology and immunohistochemical profile is recommended, particularly in limited samples (i.e., core biopsy). Applying CNV pattern as a part of a diagnostic algorithm can be potentially misleading. OPRCC is a highly variable group of tumors, which might be misdiagnosed as renal oncocytoma. Using the term OPRCC as a distinct diagnostic entity is, thanks to its high heterogeneity, questionable.

Bilateral multiple oncocytic cysts of the parotid gland in type 2 diabetes patients.

AIMS: The hallmarks of type 2 diabetes (T2D) are hyperglycaemia and insulin resistance. These factors, at the cellular level, are associated with mitochondrial dysfunction and increased glucose uptake. Such events are poorly explored in the context of the salivary glands. In this study, we present a series of eight cases of a distinct salivary gland lesion characterised by multiple oncocytic cysts, and we provide new pathological insights regarding its pathogenesis. METHODS AND RESULTS: Seven patients (87.5%) had confirmed T2D, and obesity was identified in five (62.5%) patients. Clinically, the patients showed bilateral parotid gland swelling with recurrent episodes of pain and enlargement. Imaging examination revealed multiple cystic lesions in both parotid glands. Microscopically, the parotid glands showed multiple cysts of different sizes, lined by oncocytic epithelial cells. Intraluminally, strongly eosinophilic glass-like crystalloid material was observed. Immunohistochemical studies were performed, and the most notable finding was glucose transporter 1 (GLUT1) overexpression in the oncocytic cysts which is not observed in any other oncocytic lesion of patients without T2D. In addition, high expressions of mitochondrial antigen, fission 1 protein and mitofusin-2 were observed in the oncocytic epithelium of the cysts. Furthermore, most of the oncocytic cysts showed a pattern of cytokeratin expression consistent with striated ducts. CONCLUSIONS: These results strongly suggest that T2D is associated with alterations in GLUT1 expression in the cells of striated ducts with mitochondrial dysfunction, causing a hyperplastic process characterised by multiple oncocytic cysts. For this lesion, the designation of 'diabetes-associated-bilateral multiple oncocytic cysts of the parotid gland' is proposed.

Functional and genetic studies of isolated cells from parathyroid tumors reveal the complex pathogenesis of parathyroid neoplasia.

Parathyroid adenomas (PAs) causing primary hyperparathyroidism (PHPT) are histologically heterogeneous yet have been historically viewed as largely monotypic entities arising from clonal expansion of a single transformed progenitor. Using flow cytometric analysis of resected adenomatous parathyroid glands, we have isolated and characterized chief cells, oxyphil cells, and tumor-infiltrating lymphocytes. The parathyroid chief and oxyphil cells produce parathyroid hormone (PTH), express the calcium-sensing receptor (CASR), and mobilize intracellular calcium in response to CASR activation. Parathyroid tumor infiltrating lymphocytes are T cells by immunophenotyping. Under normocalcemic conditions, oxyphil cells produce ∼50% more PTH than do chief cells, yet display significantly greater PTH suppression and calcium flux response to elevated calcium. In contrast, CASR expression and localization are equivalent in the respective parathyroid cell populations. Analysis of tumor clonality using X-linked inactivation assays in a patient-matched series of intact tumors, preparatively isolated oxyphil and chief cells, and laser-captured microdissected PA specimens demonstrate polyclonality in 5 of 14 cases. These data demonstrate the presence of functionally distinct oxyphil and chief cells within parathyroid primary adenomas and provide evidence that primary PA can arise by both clonal and polyclonal mechanisms. The clonal differences, biochemical activity, and relative abundance of these parathyroid adenoma subpopulations likely reflect distinct mechanisms of disease in PHPT.

Characterization of oncocytes in deep esophageal glands.

Deep esophageal glands play a vital role in the protection and regeneration of the esophageal mucosa. Conditions such as gastroesophageal reflux disease and Barrett's esophagus have been associated with a change in the usual glands by oncocytic metaplasia. However, little is known regarding the function of oncocytes or the relevance of this metaplastic change in the human esophagus. We hypothesized that oncocytes of deep esophageal glands also express markers characteristic of a ductal epithelial phenotype because similar oncocytes have been described as part of large ductal epithelial cells in salivary glands. We used immunohistochemical stains to define structural, functional, proliferative, and potential stem/progenitor characteristics of oncocytes. Oncocytes did not express mucins or lysozyme C, two molecules found in mucous cells and used for antimicrobial defense. Oncocytes did not express CK5, a cytokeratin found in myoepithelial cells and basal epithelial cells, but expressed CK7, a cytokeratin found in intralobular ductal epithelial cells and luminal epithelial cells of the main duct. Oncocytes expressed cystic fibrosis transmembrane conductance regulator and sodium/potassium ATPase, ion channels that play a role in bicarbonate secretion. Membrane-bound beta-catenin was detected in oncocytes, but these cells did not express the proliferative marker Ki67. Approximately, a third of oncocytes expressed SOX9 and p63, transcription factors expressed in epithelial progenitor cells in multiple organs. Moreover, oncocytes expressed CD44, a transmembrane Glycoprotein expressed in cancer stem cells. Taken together, our data show that oncocytes express markers of intralobular ductal epithelial cells and luminal epithelial cells of the main duct. Additionally, our observations suggest that oncocytes act as epithelial progenitor cells and play a role in bicarbonate secretion. Since oncocytic metaplasia is associated with conditions of chronic acid injury, it is possible that oncocytes replace the mucous cells in deep esophageal glands (dEG) as an adaptive change to counteract injury from acid reflux. The marker characterization suggests that oncocytes may originate from transdifferentiation of myoepithelial and mucous cells. This transdifferentiation might lead to an overall decrease of mucins production and secretion by the dEG and a subsequent reduction of the protection conferred by the viscoelastic mucous layer.

HURTLE CELLS IMMUNOHISTOCHEMICAL ACTIVITIES IN HASHIMOTO THYROIDITIS PARENCHYMA.

The present study was designed to evaluate the participation and utility of Hǘrtle cells morphological requirment and transformation under Hashimoto autoimmune thyroiditis versus Riedel´s struma. Several markers have been evaluated to detect induced activities of Hǘrtle cells. Study subject - specimens (tissue fragments) collected from TG surgery (thyroidectomy) for mollecular (receptor) diagnosis of Hǘrtle cells activities using routine histological and immunohistochemical samples. 89 cases were selected in Hashimoto thyroiditis diagnosis with Hǘrtle cells history (adenoma and adenomatous grouth of oncocytes). Markers as: TSH receptors, TTF-1, S-100 protein, also anti-TPO and anti-TG levels in blood plasm were detected. It was shown that solid cell claster-nests like agregation of oncocytes and adenomatous growth foci in parafollicular areas with anti-TPO and anti-TG antibodies levels arising while Riedel´s struma shown only large intra- and extra glandular inflammatory proliferative fibrosing process. Large positive expression of TTF-1 and S-100 protein and the negative reaction of TSH receptor factor suggest that Thyroid parenchyma disorganization and mollecular biological atypia with Hǘrtle cells are proceses due to hypothyreoidismus, as well as neuroectodermal cells prominent activities in 70% of Hashimoto cases.

Oxyphil cell metaplasia in the parathyroids is characterized by somatic mitochondrial DNA mutations in NADH dehydrogenase genes and cytochrome c oxidase activity-impairing genes.

Oxyphil cell transformation of epithelial cells due to the accumulation of mitochondria occurs often during cellular aging. To understand the pathogenic mechanisms, we studied mitochondrial DNA (mtDNA) alterations in the three cell types of the parathyroids using multiplex real-time PCR and next-generation sequencing. mtDNA was analyzed from cytochrome c oxidase (COX)-positive and COX-negative areas of 19 parathyroids. Mitochondria-rich pre-oxyphil/oxyphil cells were more prone to develop COX defects than the mitochondria-poor clear chief cells (P < 0.001). mtDNA increased approximately 2.5-fold from clear chief to oxyphil cells. In COX deficiency, the increase was even more pronounced, and COX-negative oxyphil cells had approximately two times more mtDNA than COX-positive oxyphil cells (P < 0.001), illustrating the influence of COX deficiency on mtDNA biosynthesis, probably as a consequence of insufficient ATP synthesis. Next-generation sequencing revealed a broad spectrum of putative pathogenic mtDNA point mutations affecting NADH dehydrogenase and COX genes as well as regulatory elements of mtDNA. NADH dehydrogenase gene mutations preferentially accumulated in COX-positive pre-oxyphil/oxyphil cells and, therefore, could be essential for inducing oxyphil cell transformation by increasing mtDNA/mitochondrial biogenesis. In contrast, COX-negative cells predominantly harbored mutations in the MT-CO1 and MT-CO3 genes and in regulatory mtDNA elements, but only rarely NADH dehydrogenase mutations. Thus, multiple hits in NADH dehydrogenase and COX activity-impairing genes represent the molecular basis of oxyphil cell transformation in the parathyroids.

Characterizing the Immune Microenvironment and Neoantigen Landscape of Hürthle Cell Carcinoma to Identify Potential Immunologic Vulnerabilities.

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.

Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma.

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.

Two distinct thyroid tumours in a patient with Cowden syndrome carrying both a 10q23 and a mitochondrial DNA germline deletion.

BACKGROUND: Cowden syndrome (CS) is an autosomal dominant disorder characterised by macrocephaly, specific mucocutaneous features and predisposition to benign and malignant tumours. Detectable mutations in the PTEN gene account for 80-85% of cases. METHODS/RESULTS: Here, the authors report a patient with macrocephaly and typical CS mucocutaneous features who developed dysplastic cerebellar gangliocytoma and two synchronous thyroid cancers of papillary and oncocytic type, in whom a germline 500-Kb deletion on chromosome 10q23 including PTEN was detected. Molecular characterisation of thyroid cancer led to the identification of the oncogenic BRAFV600E mutation in the papillary carcinoma. BRAFV600E has been proposed to cause cancer only in the presence of a tumour-suppressor mutation, which, in this case, could be the PTEN deletion. In the oncocytic carcinoma, a large deletion in the mitochondrial-DNA-encoded MTND1 was found, associated with respiratory complex I disassembly, which was subsequently shown to be a constitutional, de novo genetic lesion. CONCLUSIONS: This is the first reported case of a patient with CS carrying constitutional deletions in both the nuclear and the mitochondrial genome that might help elucidate some aspects of CS pathogenesis.

Oncocyte Membrane-Camouflaged Multi-Stimuli-Responsive Nanohybrids for Synergistic Amplification of Tumor Oxidative Stresses and Photothermal Enhanced Cancer Therapy.

The combination of various therapeutic modalities has received considerable attention for improving antitumor performance. Herein, an innovative nanohybrid, namely CaO2@FePt-DOX@PDA@CM (CFDPM), was developed for synergistic chemotherapy/chemodynamic therapy/Ca2+ overloading-mediated amplification of tumor oxidative stress and photothermal enhanced cancer therapy. Camouflage of the 4T1 cell membrane enabled CFDPM to escape the immune surveillance and accumulate in the tumor tissue. Ca2+, released from CaO2, could lead to mitochondrial dysfunction and facilitate the production of reactive oxygen species to amplify intracellular oxidative stress. Meanwhile, the increase of H2O2 concentration could enhance the efficiency of the chemodynamic therapy (CDT). Moreover, the hypoxic condition could be alleviated remarkably, which is attributed to the sufficient O2 supply by CaO2, resulting in the suppression of drug resistance and promotion of the chemotherapeutic effect. The nanohybrids involving Ca2+ overloading/CDT/chemotherapy could synergistically amplify the tumor oxidative stresses and remarkably aggravate the death of cancer cells. Significantly, the excellent photothermal conversion performance of CFDPM could further promote the tumoricidal effect. The in vitro and in vivo studies revealed that CFDPM could effectively advance the therapeutic efficiency via the cooperation of various therapeutic modalities to optimize their individual virtue, which would open a valuable avenue for effective cancer treatment.

Molecular alterations in Hürthle cell nodules and preoperative cancer risk.

Hürthle cell carcinoma (HCC) is a distinct type of thyroid cancer genetically characterized by DNA copy number alterations (CNA), typically of genome haploidization type (GH-type). However, whether CNA also occurs in benign Hürthle cell adenomas (HCA) or Hürthle cell hyperplastic nodules (HCHN), and have diagnostic impact in fine-needle aspiration (FNA) samples, remains unknown. To address these questions, we (1) analyzed 26 HCC, 24 HCA, and 8 HCHN tissues for CNA and other mutations using ThyroSeq v3 (TSv3) next-generation sequencing panel, and (2) determined cancer rate in 111 FNA samples with CNA and known surgical outcome. We identified CNA, more often of the GH-type, in 81% of HCC and in 38% HCA, but not in HCHN. Among four HCC with distant metastasis, all had CNA and three TERT mutations. Overall, positive TSv3 results were obtained in 24 (92%) HCC, including all with ATA high risk of recurrence or metastasis. Among 111 FNA cases with CNA, 38 (34%) were malignant and 73 (66%) benign. A significant correlation between cancer rate and nodule size was observed, particularly among cases with GH-type CNA, where every additional centimeter of nodule size increased the malignancy odds by 1.9 (95% CI 1.3-2.7; P = 0.001). In summary, the results of this study demonstrate that CNA characteristic of HCC also occur in HCA, although with lower frequency, and probability of cancer in nodules with CNA increases with nodule size. Detection of CNA, in conjunction with other mutations and nodule size, is helpful in predicting malignancy in thyroid nodules.

Oncocytic choroid plexus carcinoma: case report.

Herein, we report an unusual choroid plexus carcinoma with extensive oncocytic transformation. A 13-month-old girl presented with acute lethargy which quickly progressed to coma. A CT scan of the head revealed impending herniation due to hemorrhage within an intracranial tumor. An MRI scan showed a large, partly cystic and highly vascular left lateral ventricular mass. A near total resection was achieved. Microsections revealed a WHO Grade III choroid plexus carcinoma with extensive oncocyti c transformation. A minor portion of the moderately to poorly differentiated tumor exhibited classical microscopic features of choroid plexus carcinoma, including marked nuclear atypia, brisk mitotic activity (78/10 HPF), a high MIB-1 labeling index (44%) and zones of necrosis. In contrast, the large, eosinophilic, cytologically malignant but granular-appearing oncocytes comprising the majority of the lesion showed scant (1/10 HPF) mitotic activity and only a low MIB-1 labeling index (5%). A subsequent recurrence at 1 year consisted entirely of non-oncocytic tumor. Choroid plexus carcinoma with oncocytic transformation has not been previously reported. The remarkable extent of this alteration and its clinical significance remains to be determined.

Hurthle Cell Adenoma with Micro-Papillary Carcinoma and Parathyroid Adenoma in a Transplant Recipient with Graft Failure: A Case Report.

Chronic immunosuppression is known to cause an increased risk of cancers in organ transplant recipients leading to the rise in morbidity and mortality among these patients. Recent studies have observed that thyroid lesions are more frequently encountered in kidney transplant recipients. A 45-year-old woman with history of chronic hypertension, kidney transplant and graft failure, was admitted for assessment for a second renal transplant and detected to have a thyroid nodule by ultrasound (US). A fine needle aspirate (FNA) on the nodule was reported as Hurthle cell neoplasm. Histopathology revealed a Hurthle cell adenoma with an incidental micro papillary carcinoma. On follow up a year later, US investigation revealed another nodule in the inferior pole of the remnant lobe of thyroid. FNA showed sheets of uniform small round cells arranged in micro follicles, intermixed with Hurthle-like cells with absence of colloid, raising the possibility of a parathyroid lesion. Biochemical tests, clinical history, cytomorphological, immunocytochemical and biochemical tests supported a parathyroid adenoma. Advancements in diagnostic techniques and management strategies have not only improved survival rates in patients with chronic renal disease but have also identified an increasing number of multiple primary tumors in these patients. Thyroid lesions have cytomorphological similarities and may masquerade parathyroid neoplasms. Regular thyroid screening in post- transplant patients, meticulous pathological examination and parathormone assay are crucial in the early diagnosis, management and prevention of morbidity and mortality in these patients. Keywords: Fine needle aspiration, kidney transplant, Hurthle cell neoplasm, parathyroid adenoma, micropapillary carcinoma.

The Oncocytic Variant of Poorly Differentiated Thyroid Carcinoma Shows a Specific Immune-Related Gene Expression Profile.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) is a rare, follicular cell-derived neoplasm with an unfavorable prognosis. The oncocytic variant of PDTC may be associated with even more adverse outcome than classical PDTC cases, but its specific molecular features are largely unknown. Our aim was to explore the immune-related gene expression profile of oncocytic and classical PDTC, in correlation with clinical and pathological characteristics (including programmed death ligand 1 [PD-L1] expression) and outcome, and in comparison with a control group of well-differentiated follicular carcinomas (WDFCs), including conventional follicular carcinomas (FTCs) and Hürthle cell carcinomas (HCCs). METHODS: A retrospective series of 48 PDTCs and 24 WDFCs was analyzed by means of NanoString technology employing the nCounter PanCancer Immune Profiling panel. Gene expression data were validated using quantitative real-time polymerase chain reaction. RESULTS: Oncocytic PDTCs showed a specific immune-related gene expression profile, with higher expression of LAIR2, CD274, DEFB1, IRAK1, CAMP, LCN2, LY96, and APOE, and lower expression of NOD1, as compared to conventional PDTCs. This molecular signature was associated with increased intratumoral lymphocytic infiltration, PD-L1 expression, and adverse outcome. Three of these genes, CD274, DEFB1, and IRAK1, as well as PD-L1 expression, were also the hallmarks of HCCs as compared to FTCs. By contrast, the panel of genes differentially regulated in PDTCs as compared to WDFCs was unrelated to the oncocytic phenotype. CONCLUSIONS: Our results revealed a distinctive immune-related gene expression profile of oncocytic PDTC and confirmed a more aggressive outcome in this cancer subtype. These findings may provide guidance when exploring novel immunotherapeutic options for oncocytic PDTC patients.

Oncocytic versus mitochondrion-rich follicular thyroid tumours: should we make a difference?

AIMS: To separate true oncocytic neoplasms from mitochondrion-rich non-oncocytic lesions based on the intracellular relationship between major cell organelles, and to establish the diagnostic and clinical relevance of this distinction. METHODS AND RESULTS: Tissue samples from 276 follicular adenomas, 194 follicular carcinomas, 162 normal thyroids and 296 non-neoplastic lesions were classified as conventional, mitochondrion-rich or oncocytic based on the immunohistochemically assessed quantity and intracellular distribution of mitochondria and endoplasmic reticulum (ER) and nuclear position. Pathological and clinical features were compared among the groups. In oncocytes, densely packed mitochondria resulted in homogeneous immunolabelling of basal cytoplasmic regions, whereas ER and the nuclei were typically displaced to the apical position. This aberrant organelle distribution was not observed in non-oncocytes, which allowed reliable distinction between oncocytic and mitochondrion-rich lesions. Clinically, mitochondrial increase in non-oncocytic lesions was associated with neoplasia, malignancy and higher cancer recurrence rates. Similar correlation, albeit less pronounced, was observed within the oncocytic tumour group. By contrast, oncocytic change per se was not associated with neoplasia, malignancy or cancer aggressiveness. CONCLUSIONS: True oncocytic neoplasms can be distinguished from mitochondrion-rich non-oncocytic tumours based on aberrant distribution of all major cell organelles. This distinction has immediate clinical relevance and should be implemented in practice.

Hurthle cell predominance impacts results of Afirma gene expression classifier and ThyroSeq molecular panel performance in indeterminate thyroid nodules.

BACKGROUND: Molecular tests such as the Afirma gene expression classifier (GEC) and mutational panels (such as ThyroSeq) have been introduced to help risk stratify cytologically indeterminate thyroid nodules with the aim to reduce the number of unnecessary thyroidectomies. Some reports have suggested that samples with Hurthle cell predominance have higher false-positive rates on GEC testing, but data are limited. METHODS: We reviewed thyroid nodules with indeterminate (Bethesda III/IV) cytology at our institution. Patient demographics, cytologic and histologic diagnoses (where available), and molecular test results were collected. RESULTS: GEC was performed on 202 nodules, and ThyroSeq was performed on 81 nodules. In the GEC cohort, 66% of nodules with Hurthle cell predominance yielded "suspicious" result vs 46% of nodules without Hurthle cell predominance, with risk of malignancy (ROM) for surgically resected nodules of 16% and 33%, respectively. In ThyroSeq cohort, 8% of nodules with Hurthle cell predominance yielded a high-risk mutation vs 19% of nodules without Hurthle cell predominance, with ROM of 50% and 33%, respectively. CONCLUSIONS: For ThyroSeq molecular panel, while it did not appear that there was an increase in rate of high-risk mutations detected in the samples with Hurthle cell predominance, small numbers limit the generalizability of these results. For the GEC cohort, indeterminate thyroid nodules with predominance of Hurthle cells showed an increased rate of "suspicious" results compared to samples without Hurthle cell predominance. The ROM for GEC "suspicious" nodules with Hurthle cell predominance on surgical resection was lower in our study. Repeat FNA may be of use in patients with these types of nodules. In the context of a Hurthle cell predominant lesion, positive results on molecular testing may not carry a high rate of malignancy.

FDG-Avid Hürthle Cell Thyroid Adenoma.

Incidental thyroid uptake is found in approximately 2.5% of patients who undergo FDG PET for nonthyroid malignancy; approximately a third of the FDG PET thyroid incidentalomas are malignant, including primary thyroid malignancies and metastasis. We describe a 50-year-old woman, a potential heart transplant candidate with history of breast cancer, who was found by FDG PET/CT to harbor a large thyroid mass with intense FDG uptake. Biopsy and molecular study demonstrated that the thyroid mass was a Hürthle cell adenoma. This case highlights that Hürthle cell neoplasm should be included in the differential diagnosis of a thyroid nodule with very high FDG avidity.

Hürthle cell lesions on thyroid fine needle aspiration cytology: Molecular and histologic correlation.

BACKGROUND: Hürthle cell lesions often pose diagnostic challenges, despite their common occurrence on thyroid fine-needle aspiration cytology (FNAC). The associated molecular alterations are also not well understood. Therefore, our study aimed to delineate the molecular profile of Hürthle cell lesions classified as Bethesda Categories III or IV (atypia of undetermined significance (AUS) or suspicious for follicular neoplasm (SFN)) on FNAC and to correlate this molecular profile with surgical resection findings. METHODS: This study consisted of 188 Hürthle cell lesions with indeterminate cytology and ThyroSeq® v2/v3 molecular testing results. Surgical follow-up was available for 33 cases. RESULTS: The majority of indeterminate Hürthle cell lesions had negative ThyroSeq® results (61%) and were benign on available surgical follow-up. The most prevalent mutations involved the RAS gene (21%), which were associated with benign lesions, non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), and malignancy. The remaining mutations involved less than 18% of the cases, including PAX8/PPARG (3.7%), TSHR (3.7%), EIF1AX (2.7%), MET (2.1%), PTEN (1.6%), clonal copy number alteration (1.6%), TERT (1.1%), and 0.5% each of GNAS, PIK3CA, and TP53 mutations. On follow-up, 45% were benign, 24% were NIFTP, and 30% were malignant. The malignant cases had different molecular alterations. CONCLUSION: No single molecular alteration defines cytologically indeterminate Hürthle cell lesions; the majority of cases have low-risk or no molecular alterations and are benign on follow-up. These findings suggest that molecular testing may be useful, but is not definitive, in determining which cases may be managed conservatively; additional studies are needed to fully determine the negative predictive value in ruling out malignancy.