Advancing parathyroid anatomy understanding through single-cell RNA sequencing in uremic secondary hyperparathyroidism.

This commentary explores the recent application of single-cell RNA sequencing in the study of uremic secondary hyperparathyroidism, shedding light on the cellular dynamics within parathyroid glands. The use of single-cell RNA sequencing reveals new insights into the differentiation processes of chief and oxyphil cells, challenging traditional views and highlighting the potential of this technology in advancing our understanding of parathyroid anatomy.

N-Nitrosomorpholine-induced oncocytic transformation in rat endocrine organs.

BACKGROUND: N-Nitrosomorpholine (NMO) is one of the most common N-nitroso compounds. An oncocytic transformation has been demonstrated in renal tubules of NMO-treated rats. In our study, we aimed to investigate the potential transformation of oncocytic cells in 6 endocrine organs, i.e., thyroid, adrenal and pituitary glands, pancreas, testis, and bone, of NMO-exposed rats. METHODS: Thirty male rats were born and raised. Fifteen of them were given a single dose of 320 mg NMO per kg body weight, dissolved in drinking water, by a gavage tube. At the end of 52 weeks, the animals in both series were killed. Right after the killing, 6 different endocrine organs (hypophysis, thyroid, pancreas, adrenal gland, bone [femur], and testicles) of each animal were excised. RESULTS: There was no evidence of oncocytic cell development in the control group. In contrast, oncocytes were observed in 8 out of 13 NMO-treated rats: 2 in the adrenal sections, 1 in the thyroid sections, 3 in the pituitary sections, and 2 in the pancreas sections. Thesticle and bone sections were completely normal. CONCLUSIONS: We showed that NMO induced an oncocytic change in pancreas, thyroid, pituitary, and adrenal glands. To date, no identified specific environmental risk factors that lead to an oncocytic transformation in endocrine glands have been reported previously. Given the increasing prevalence of endocrine-disrupting chemicals in the environment, personal care products, manufactured goods, and food sources, there is a need to advance our understanding of the pathological mechanisms underlying oncocytosis in endocrine organs.

Molecular-derived risk of malignancy and the related positive call rate of indeterminate thyroid cytology diagnoses as quality metrics for individual cytopathologists.

BACKGROUND: Indeterminate thyroid cytopathology diagnoses represent differing degrees of risk that are corroborated by follow-up studies. However, traditional cytologic-histologic correlation may overestimate the risk of malignancy (ROM) because only a subset of cases undergo resection. Alternatively, some molecular tests provide probability of malignancy data to calculate the molecular-derived risk of malignancy (MDROM) and the positive call rate (PCR). The authors investigated MDROMs and PCRs of indeterminate diagnoses for individual cytopathologists as quality metrics. METHODS: This study was approved by the Department of Pathology Quality Improvement Program. Thyroid cytopathology diagnoses and ThyroSeq v3 results were retrieved for each cytopathologist for a 2-year period with at least 3 years of follow-up for the atypia of undetermined significance (AUS), follicular neoplasia (FN), and follicular neoplasia, oncocytic-type (ONC) cytopathologic diagnoses. MDROMs and PCRs were compared with reference ROMs and cytologic-histologic correlation outcomes. RESULTS: The overall MDROMs (and ranges for cytopathologists) for the AUS, FN, and ONC categories were 13.4% (range, 5.8%-20.8%), 28.1% (range, 22.1%-36.7%), and 27.0% (range, 19.5%-41.5%), respectively, and most individual cytopathologists' MDROMs were within reference ROM ranges. However, PCRs more effectively parsed the differences in cytopathologists' ROM performance. Although the overall PCRs were not significantly different across cytopathologists (p = .06), the AUS PCRs were quite different (p = .002). By cytologic-histologic correlation, six of 55 resected cases (10.9%) were falsely negative, and there were no false-positive cases. CONCLUSIONS: MDROMs and PCRs evaluate concordance with reference ROMs and with one another and provide individual feedback, which potentially facilitates quality improvement.

Single-cell RNA sequencing reveals transdifferentiation of parathyroid chief cells into oxyphil cells in patients with uremic secondary hyperparathyroidism.

The parathyroid gland is one of the main organs that regulate calcium and phosphorus metabolism. It is mainly composed of chief cells and oxyphil cells. Oxyphil cell counts are low in the parathyroid glands of healthy adults but are dramatically increased in patients with uremia and secondary hyperparathyroidism (SHPT). Increased oxyphil cell counts are related to drug treatment resistance, but the origin of oxyphil cells and the mechanism of proliferation remain unknown. Herein, three types of parathyroid nodules (chief cell nodules, oxyphil cell nodules and mixed nodules, respectively) excised from parathyroid glands of uremic SHPT patients were used for single-cell RNA sequencing (scRNA-seq), other molecular biology studies, and transplantation into nude mice. Through scRNA-seq of parathyroid mixed nodules from three patients with uremic SHPT, we established the first transcriptomic map of the human parathyroid and found a chief-to-oxyphil cell transdifferentiation characterized by gradual mitochondrial enrichment associated with the uremic milieu. Notably, the mitochondrial enrichment and cellular proliferation of chief cell and oxyphil cell nodules decreased significantly after leaving the uremic milieu via transplantation into nude mice. Remarkably, the phenotype of oxyphil cell nodules improved significantly in the nude mice as characterized by decreased mitochondrial content and the proportion of oxyphil cells to chief cells. Thus, our study provides a comprehensive single-cell transcriptome atlas of the human parathyroid and elucidates the origin of parathyroid oxyphil cells and their underlying transdifferentiating mechanism. These findings enhance our understanding of parathyroid disease and may open new treatment perspectives for patients with chronic kidney disease.

Diagnostic performance of molecular testing in indeterminate (Bethesda III and IV) thyroid nodules with Hürthle cell cytology.

BACKGROUND: Indeterminate thyroid nodules with Hürthle cell cytology remain a diagnostic challenge. The low benign call rate and positive predictive value of first-generation molecular tests precluded their use to rule out malignancy. We examined the diagnostic performance of current tests. METHOD: This subset analysis of our prospective randomized trial compared the benign call rate and positive predictive value of Afirma Gene Sequencing Classifier and Thyroseq v3 in Bethesda III and IV nodules with Hürthle cell cytology. Molecular test samples were obtained at initial fine-needle aspiration (8/2017-7/2022) and reflexively sent for processing. RESULTS: Molecular testing was performed on 140 Hürthle cell nodules. Of 79 nodules tested with the Afirma Gene Sequencing Classifier, the benign call rate was 84% (66/79). Nine of 66 nodules with benign results were resected, with no malignancies. Twelve of 13 nodules with suspicious results were resected, revealing 3 malignancies-2 papillary thyroid carcinomas and one Hürthle cell carcinoma (positive predictive value 25%). Of 61 nodules tested with Thyroseq v3, the benign call rate was 56% (34/61; (P < .01 versus Afirma Gene Sequencing Classifier). Five of 34 nodules with negative results were resected, with no malignancies. Nineteen of 27 nodules with positive results were resected, revealing 3 malignancies-2 papillary thyroid carcinomas and 1 Hürthle cell carcinoma (positive predictive value 16%). CONCLUSION: The high benign call rate of current molecular tests in Hürthle cell nodules strengthens their value in enabling patients to avoid surgery.

Papillary cystadenoma of the major salivary gland: A case report and review of literature.

Papillary cystadenoma (PC) of the salivary gland is an uncommon benign epithelial neoplasm that shows predominantly multicystic growth pattern with intraluminal papillary proliferation and areas of oncocytic differentiation. We report a case of papillary cystadenoma of the parotid gland in a 44-years-old female. The patient presented with painful nodular swelling in the right parotid region for two months. Ultrasonography revealed a well marginated oval lesion with altered signal intensity involving the superficial lobe. The excision specimen showed a neoplasm with multicystic spaces having papillary projections lined by benign low-grade epithelium and supported by fibrovascular cores. No significant cytological atypia or mitosis was observed. The cells were immunoreactive for Keratin, Keratin 7, and were negative for Keratin 20, AR, HeR2/neu, TTF1, CDX2, and GATA3. p63 and Keratin 5/6 highlighted the myoepithelial cell layer lining the cystic spaces as well as the papillary projections. The Ki-67 proliferation index was 6%. The patient is on close clinical and imaging follow-up for the last 1year and 8 months without any evidence of disease recurrence or metastasis. Rarity of the lesion and distinct histomorphology warrants appropriate knowledge and discussion of the subject.

Thyroglobulin as a Rapid and Cost-Effective Biomarker for Diagnosis of Thyroid Carcinoma Brain Metastasis: A Case Report of a Patient with Metastatic Hurthle Cell Thyroid Carcinoma.

BACKGROUND Brain metastasis of papillary thyroid cancer (PTC) is rare. Treatment of these patients is challenging due to the lack of specific guidelines. Early diagnosis is accompanied by immediate treatment and less morbidity. Total resection of brain lesions may be unattainable when they include infiltration of eloquent areas. This report is of an 81-year-old man who had undergone total thyroidectomy for goiter in the past and presented with metastatic papillary thyroid carcinoma (PTC) to the neck after a gap of 16 years. After two years, the patient developed a solitary cystic brain PTC metastasis associated with raised thyroglobulin (Tg) inside the cystic lesion aspirated during brain surgery. CASE REPORT An 81-year-old male patient was admitted for a space-occupying brain lesion in the right frontal lobe. The patient's history included metastatic disease of PTC to the neck with cervical lymph node metastasis and local recurrence after surgery and radioactive iodine-131 treatment. The patient underwent craniotomy and removal of the lesion. The aspirated fluid was sent for cytological examination and measurement of Tg levels, which were interestingly high. Pathology of the brain lesion revealed infiltration of brain parenchyma from a metastatic lesion characterized by eosinophilic cells with irregular contours forming grooves, resulting in cytoplasmic pseudo-inclusions, an oncotic variant of PTC. CONCLUSIONS This report has shown that residual tissue may be present following total thyroidectomy and may be the origin of PTC with metastasis to the brain. The patient in this study suffered from a brain lesion that could be excised. However, aspiration of cystic compartments could provide a rapid diagnosis in patients with non-removable brain lesions.

"Copy number alteration" as the sole molecular finding of a Thyroseq test is more commonly seen in Hurthle cell neoplasms.

BACKGROUND: To better understand the molecular alterations associated with Hurthle cell lesions of the thyroid, we retrospectively reviewed the association of clonal DNA copy number alterations (CNAs) with fine needle aspiration (FNA) cytomorphology and surgical follow-up. METHODS: Hurthle cell type (HCT) and non-Hurthle cell type (NHCT) thyroid FNAs that were classified according to the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) as atypia of undetermined significance (AUS) and suspicious for a follicular neoplasm (SFN) with corresponding molecular testing performed by ThyroSeq v3 genomic classifier were compared to surgical follow-up. RESULTS: A total of 54 thyroid FNA cases were identified, distributed among the following categories: AUS-HCT (n = 15, 27.8%), SFN-HCT (n = 11, 20.4%), AUS-NHCT (n = 19, 35.2%), and SFN-NHCT (n = 9, 16.6%). The lesions classified as AUS-HCT and SFN-HCT showed a higher prevalence of CNAs (n = 10/26; 38.5%) compared to their NHCT counterparts (n = 3/28; 10.7%) (p < .03). Of the 42 patients (77.8%) with surgical follow-up, CNAs were more often seen in benign (n = 10/26, 38.5%) than malignant conditions (n = 1/16, 6.3%) (p < .03). CNAs were encountered in more lesions with Hurthle cell features on histologic examination (n = 8/14, 57.1%) than those without (n = 3/28, 10.7%) (p < .002). The presence of CNAs alone was seen only in benign adenomas and more commonly with Hurthle cell features (n = 5/7, 71.4%). CONCLUSION: In this study, CNAs were associated with Hurthle cell morphology on thyroid FNA and benign adenomas upon surgical follow-up. Therefore, if the only finding of a positive ThyroSeq v3 GC result is a CNA, conservative management can be considered if clinically indicated.

Oncocytic sialolipoma of parotid gland: Case report and literature review.

Neoplastic lipomatous lesions of the salivary glands constitute ≤0.5% of all the salivary gland tumors. Oncocytic sialolipoma of the parotid glands is extremely uncommon. We report a case of oncocytic sialolipoma of the parotid gland in a 59-year-old male who presented with a gradually increasing swelling of the right parotid. Excisional parotid biopsy performed in view of possible pleomorphic adenoma as suggested on ultrasonography showed histological features consistent with oncocytic sialolipoma. We also described the characteristics of 24 previously reported cases of oncocytic sialolipoma of the parotid gland. The median age of the patients including the present case was 56 years (range 7-89), and 14 were male. The largest and the least reported sizes of the tumor were 7.0 and 1.4 cm, respectively. The left-sided parotid gland was more commonly involved (14/23). Despite its rarity, oncocytic sialolipoma should be considered in lipomatous parotid lesions showing epithelial components with oncocytic changes.

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.

Clinico-cytopathological subcategorization in thyroid nodules of atypia of undetermined significance/follicular lesion of undetermined significance using the TIRADS and Bethesda classifications.

Introduction: Bethesda category III - atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is a heterogeneous class of the Bethesda system for thyroid nodules. In order to clarify the therapeutic road for clinicians, this category was subclassified based on the cytopathological features. In this study, we evaluated the risk of malignancy, surgical outcome, demographic characteristics, and correlation of ultrasound features with the final outcome in patients with thyroid nodules based on AUS/FLUS subclassification. Method: After evaluating 867 thyroid nodules from three different centers, 70 (8.07%) were initially diagnosed as AUS/FLUS. The cytopathologists re-interpreted the FNA samples and subclassified them into five subcategories: architectural atypia, cytologic atypia, cytologic and architectural atypia, and Hürthle cell AUS/FLUS, and atypia, which was not specified. Based on the suspicious ultrasound features, an appropriate ACR TI-RADS score was allocated to each nodule. Finally, the malignancy rate, surgical outcomes, and ACR TI-RADS scores were evaluated among Bethesda category III nodules. Results: Among the 70 evaluated nodules, 28 (40%) were subclassified as Hürthle cell AUS/FLUS, 22 (31.42%) as cytologic and architectural atypia, 8 (11.42%) as architectural atypia, 7 (10%) as cytologic atypia, and 5 (7.14%) as atypia which was not specified. The overall malignancy rate was 34.28%, and the architectural atypia and Hürthle cell nodules displayed lower malignancy compared to other groups (P-Value<0.05). Utilizing ACR TI-RADS scores showed no statistical significance between Bethesda III subcategorization and ACR TI-RADS scores. However, ACR TI-RADS can be a reliable predictor for Hürthle cell AUS/FLU nodules. Conclusion: ACR TI-RADS helps evaluate malignancy only in the Hürthle cell AUS/FLUS subcategory of AUS/FLUS. Besides, cytopathological reporting based on the suggested AUS/FLUS subclassification could help clinicians take appropriate measures to manage thyroid nodules.

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.

Top Ten Oncocytic Head and Neck Lesions to Contemplate.

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.

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.

Thyroid Oncocytic (Hürthle Cell) Nodules With Longitudinal Nuclear Grooves: Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 15 Cases.

CONTEXT.­: Thyroid nodules with longitudinal nuclear grooves have been widely regarded as synonymous with papillary thyroid carcinoma (PTC). OBJECTIVE.­: To study a series of cases of thyroid nodules that exhibited oncocytic (Hürthle cell) features and contained longitudinal nuclear grooves yet failed to display aggressive behavior or the full features of papillary thyroid carcinoma. DESIGN.­: The clinicopathologic, immunohistochemical, and molecular genetic features of 15 patients with these features were studied. Next-generation sequencing was performed to examine 161 genes for oncogenic driver alterations associated with thyroid neoplasia. RESULTS.­: The lesions occurred in 11 women and 4 men aged 27 to 80 years and measured 0.2 to 2.3 cm in diameter (mean, 1.1 cm). The tumors were well circumscribed and noninvasive and showed a proliferation of large cells with abundant granular cytoplasm and centrally placed nuclei displaying scattered longitudinal nuclear grooves. Immunohistochemical stains were negative for HBME-1, galectin-3, and CK19 in all cases. NRAS pQ61R was detected in 6 cases, KRAS p.Q61E in 1 case, and AKT2 p.E17K in 1 case. None of the genetic changes classically associated with conventional PTC or with high-grade thyroid malignant neoplasms were identified. Clinical follow-up in 9 patients showed no evidence of recurrence or metastases between 2 and 13 years (mean, 5.7 years). CONCLUSIONS.­: Longitudinal nuclear grooves can be occasionally encountered in oncocytic (Hürthle cell) tumors and should not lead to a diagnosis of PTC in the absence of other features supporting that diagnosis.

Significance of oncocytic features in poorly differentiated thyroid carcinoma - a bi-institutional experience.

Poorly differentiated thyroid carcinoma (PDTC), defined by Turin criteria, comprises a subset of high-grade follicular-derived thyroid carcinomas with intermediate prognosis. While differentiated oncocytic thyroid carcinomas demonstrate clinicopathologic and genetic differences compared to their non-oncocytic counterparts, similar data is limited in oncocytic (Hurthle) PDTCs (OPDTCs). Here, we assessed the impact of various oncocytic cut-offs in PDTCs on clinical, histologic and survival parameters.Our bi-institutional cohort comprised 210 primary PDTCs with available slides reviewed by at least one pathologist. Histologic features, including oncocytic fraction, were recorded. Clinicopathologic data were obtained, including overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), locoregional recurrence free survival (LRRFS), and distant metastasis-free survival (DMFS). Radioactive iodine avidity data was available for 125 PDTCs based on postoperative whole-body scanning.Within our cohort, 39.0% PDTCs had any oncocytic component with 24.8% meeting the 75% World Health Organization (WHO) oncocytic definition. Any oncocytic component and > 25% oncocytic cut-off correlated with decreased DSS and LRRFS, respectively, compared to non-oncocytic PDTCs (NOPDTCs) on univariate and multivariate analysis. The 100% oncocytic cut-off was significant for DSS on univariate analysis but a non-significant trend on multivariate analysis. Any oncocytic cut-off (100%, > 75%, > 50%, > 25%, or > 0%) conferred higher radioactive iodine (RAI)-refractoriness to OPDTCs compared to NOPDTCs. NF1 and PTEN alterations were enriched in OPDTCs (40% vs. 0%, and 60% vs 8%, respectively), whereas NRAS mutations were frequent in NOPDTCs (47% vs. 7%).Among PDTCs, the presence of oncocytes led to downward trend in all outcome parameters, especially for DSS and LRRFS. OPDTCs were enriched in NF1 and PTEN mutations. Consistently, all oncocytic cut-offs were associated with RAI-refractoriness. Accordingly, additional studies are needed to reassess the current 75% cut-off used to define oncocytic thyroid lesions.

Oncocytic nodular hyperplasia of the thyroid.

Nodular hyperplasia of the thyroid is a process whereby the gland experiences growth by nodular expansion of thyroid parenchyma. We have encountered 45 patients in whom the process was caused by the growth of well-defined and sharply circumscribed but unencapsulated nodules composed of oncocytic thyroid follicular cells. The lesions arose in 39 women and 6 men, aged 25-69 years (mean = 50.3 years). The surrounding thyroid parenchyma showed features of chronic lymphocytic thyroiditis. The nodules varied from microscopic to 5 cm and appeared to compress the surrounding thyroid parenchyma. Most of the lesions lacked a well-defined capsule. In 26 tumors, the nodules displayed a predominantly follicular pattern of growth; in 8 cases there were admixtures of follicular and trabecular patterns with focal solid areas devoid of follicles. Clinical follow-up in 39 patients ranging from 7 to 22 years (median = 16 years) showed no evidence of recurrence, metastasis, or malignant transformation. One patient died of unknown causes 15 years after the diagnosis, and another patient died 4 years after diagnosis from metastatic colonic adenocarcinoma. Oncocytic nodular hyperplasia is a benign process associated with chronic lymphocytic thyroiditis that should be distinguished from benign and malignant oncocytic (Hurthle cell) tumors of the thyroid.

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.

Prognostic factors and survival analysis of Hurthle cell carcinoma: A population-based study.

BACKGROUND: Hurthle cell carcinoma is a rare type of differentiated thyroid cancer and historically associated with a worse prognosis. The aim of this study was to define the demographic and socioeconomic factors, tumor characteristics, and surgical treatment status associated with Hurthle cell carcinoma survival using the most recent population-level data. METHODS: The Surveillance, Epidemiology, and End Results database was queried for adult patients (>18 years of age) diagnosed with Hurthle cell carcinoma from 2000 to 2018. The demographic factors, socioeconomic factors, tumor characteristics, and extent of surgery data were collected as potential predictors. The outcomes of interest were 10-year overall and disease-specific survival, which were estimated using the Kaplan-Maier method. The associations between the potential predictors and survival were evaluated using the Cox proportional hazard model. RESULTS: In total, 4,643 patients with Hurthle cell carcinoma were identified using the Surveillance, Epidemiology, and End Results database. The cohort was predominately White, had a mean age of 57.7 (±15.6), 69% female sex, and median follow-up was 90 months. The 10-year overall survival and Hurthle cell carcinoma-specific survival were 78.1% (95% confidence interval: 76.7%-79.5%) and 91.8% (95% confidence interval: 90.9%-92.9%), respectively. Younger age <55 years, female sex, White race, Hispanic ethnicity, higher household income, and lower tumor grade and stage were significantly associated with increased survival (P < .01). In the multivariate Cox proportional hazard model, all variables except race and ethnicity remained significantly associated with overall survival. Although patients who underwent thyroid surgery had improved survival compared to no surgery, the extent of surgery did not have any effect on their overall or disease-specific survival. CONCLUSION: This study highlighted the aggressive nature of Hurthle cell carcinoma and the effect of socioeconomic factors, such as household income, which may play a role in Hurthle cell carcinoma survivorship. Research is needed to understand the interplay of these factors and their role in predicting patient outcomes.