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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 -
Cancer Cytopathology Dec 2020The goal of this study was to evaluate the morphology, immunoprofile, and management of renal oncocytoma (RO), hybrid oncocytic tumor (HOT), and chromophobe renal cell...
BACKGROUND
The goal of this study was to evaluate the morphology, immunoprofile, and management of renal oncocytoma (RO), hybrid oncocytic tumor (HOT), and chromophobe renal cell carcinoma (ChRCC).
METHODS
Forty-seven cases of RO, 7 cases of HOT, and 25 cases of ChRCC were included in the study. Tissue microarrays were prepared for immunohistochemical evaluation.
RESULTS
Large sheets of cells with transverse vessels, and higher nuclear grade were seen more often in ChRCC than in RO or HOT. Tumor cells of RO were more uniform in size and shape relative to HOT and ChRCC. The cytoplasmic features of RO were more uniformly granular relative to HOT and ChRCC, which exhibited variable cytoplasmic features. CK7 and MUC1 were expressed more frequently and diffusely in ChRCC (54% and 94%, respectively) than RO (4% and 52%, respectively) and HOT (0% and 71%, respectively). AMACR and PAX8 were more frequently expressed diffusely in RO (67% and 42%, respectively) than in HOT (0% and 0%, respectively) or ChRCC (14% and 11%, respectively). Most HOT (57%) and CHRCC (60%) patients underwent nephrectomy. Cryoablation was the treatment of choice for 24% of patients with ChRCC, 2% of patients with RO, and 0% of patients with HOT. The majority of patients with RO (88%) opted for active surveillance-a much higher rate than that for patients with HOT (29%) or ChRCC (12%).
CONCLUSION
Some cytologic features and immunomarkers are useful in differentiating RO, HOT, and ChRCC. Because no immunomarker or morphologic finding is specific by itself, a combination of morphologic features with immunohistochemistry appears to be the most reliable way to distinguish ChRCC, HOT, and RO on biopsy samples. Subclassification of renal oncocytic tumors into specific categories impacts clinical management and downstream treatment selection.
Topics: Adenoma, Oxyphilic; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Biopsy, Fine-Needle; Carcinoma, Renal Cell; Cytodiagnosis; Diagnosis, Differential; Disease Management; Female; Follow-Up Studies; Humans; Immunohistochemistry; Kidney Neoplasms; Male; Middle Aged; Nephrectomy; Prognosis; Retrospective Studies
PubMed: 32697415
DOI: 10.1002/cncy.22330 -
European Annals of Otorhinolaryngology,... Nov 2015Fine-needle aspiration cytology (FNAC) of thyroid nodules commonly reveals the presence of oncocytic cells (or Hürthle cells) in a follicular neoplasm. Histological...
INTRODUCTION
Fine-needle aspiration cytology (FNAC) of thyroid nodules commonly reveals the presence of oncocytic cells (or Hürthle cells) in a follicular neoplasm. Histological examination is necessary to determine the benign or malignant nature of the tumour. However, oncocytic cells are also normally present in the parathyroid glands.
CASE REPORT
A thyroid nodule was discovered on thyroid ultrasound in a woman with a history of left partial thyroid lobectomy. Fine-needle aspiration cytology revealed a follicular neoplasm comprising oncocytic cells (Hürthle cells). This woman also presented features of hyperparathyroidism with hypercalcaemia. (123)I/(99m)Tc-sestamibi and (18)F-fluorocholine PET-CT scan revealed increased uptake over the remaining left thyroid lobe. Left lobectomy was completed together with thyroid exploration. Histological examination revealed a parathyroid adenoma in the residual thyroid tissue. Parathyroid hormone levels subsequently returned to normal.
DISCUSSION
Cytomorphological similarities are often observed between parathyroid and Hürthle cell thyroid tumours. The parathyroid rather than thyroid nature of the tumour must be strongly suspected preoperatively in the presence of hyperparathyroidism.
Topics: Adenoma; Female; Humans; Hyperparathyroidism; Middle Aged; Multimodal Imaging; Oxyphil Cells; Parathyroid Neoplasms; Positron-Emission Tomography; Tomography, X-Ray Computed
PubMed: 26364541
DOI: 10.1016/j.anorl.2015.08.033 -
Archives of Pathology & Laboratory... Nov 2014Eosinophilic renal neoplasms include a spectrum of solid and papillary tumors ranging from indolent benign oncocytoma to highly aggressive malignancies. Recognition of... (Review)
Review
CONTEXT
Eosinophilic renal neoplasms include a spectrum of solid and papillary tumors ranging from indolent benign oncocytoma to highly aggressive malignancies. Recognition of the correct nature of the tumor, especially in biopsy specimens, is paramount for patient management.
OBJECTIVE
To review the diagnostic approach to eosinophilic renal neoplasms with light microscopy and ancillary techniques.
DATA SOURCES
Review of the published literature and personal experience.
CONCLUSIONS
The following tumors are in the differential diagnosis of oncocytic renal cell neoplasm: oncocytoma, chromophobe renal cell carcinoma (RCC), hybrid tumor, tubulocystic carcinoma, papillary RCC, clear cell RCC with predominant eosinophilic cell morphology, follicular thyroid-like RCC, hereditary leiomyomatosis-associated RCC, acquired cystic disease-associated RCC, rhabdoid RCC, microphthalmia transcription factor translocation RCC, epithelioid angiomyolipoma, and unclassified RCC. In low-grade nonpapillary eosinophilic neoplasms, distinction between oncocytoma and low-grade RCC mostly rests on histomorphology; however, cytokeratin 7 immunostain may be helpful. In high-grade nonpapillary lesions, there is more of a role for ancillary techniques, including immunohistochemistry for cytokeratin 7, CA9, CD10, racemase, HMB45, and Melan-A. In papillary eosinophilic neoplasms, it is important to distinguish sporadic type 2 papillary RCC from microphthalmia transcription factor translocation and hereditary leiomyomatosis-associated RCC. Histologic and cytologic features along with immunohistochemistry and fluorescence in situ hybridization tests for TFE3 (Xp11.2) and TFEB [t(6;11)] are reliable confirmatory tests. Eosinophilic epithelial neoplasms with architecture, cytology, and/or immunoprofile not qualifying for either of the established types of RCC should be classified as unclassified eosinophilic RCC and arbitrarily assigned a grade (low or high).
Topics: Adenoma, Oxyphilic; Angiomyolipoma; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Carcinoma, Renal Cell; Chromosomes, Human, X; Eosinophilia; Female; Humans; Kidney Diseases, Cystic; Kidney Neoplasms; Leiomyomatosis; Male; Microphthalmia-Associated Transcription Factor; Neoplastic Syndromes, Hereditary; Skin Neoplasms; Translocation, Genetic; Uterine Neoplasms
PubMed: 25357116
DOI: 10.5858/arpa.2013-0653-RA -
Current Opinion in Oncology Jan 2024The assessment of thyroid nodules is a common clinical problem, linked to the high incidence of thyroid nodules in the population and the low incidence of aggressive... (Review)
Review
PURPOSE OF REVIEW
The assessment of thyroid nodules is a common clinical problem, linked to the high incidence of thyroid nodules in the population and the low incidence of aggressive thyroid carcinoma. The screening is therefore one of the strengths of our patient care. Recently, the 2023 Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) and 2022 WHO classification of thyroid neoplasms have been released based on the definition of new entities and the growing impact of molecular testing. The aim of this review is to analyze how these upgrades can help us in the daily routine practice diagnosis of thyroid cancer.
RECENT FINDINGS
Our review is focused on the most frequent thyroid tumors derived from thyroid follicular cell. Fine needle aspiration (FNA) is the gold standard for the screening of thyroid nodules with very high levels of sensitivity and specificity. These sensitivity and specificity are improved by molecular testing, which refines the risk of malignancy. The 2023 TBSRTC integrates molecular data and the upgrades integrated in the 2022 WHO classification such as the 'low-risk neoplasms' and the 'high-grade follicular-cells derived carcinoma'. The morphological examination remains crucial since the capsular and/or vascular invasion are key features of malignancy in the follicular thyroid neoplasms. Low-risk neoplasms represent a clinical challenge since no specific guidelines are available. Challenges remain regarding oncocytic thyroid lesions, which are not associated with specific diagnostic molecular biomarkers. Molecular testing can help not only in deciphering the prognosis but also in the targeted therapeutic strategy.
SUMMARY
While molecular testing has succeeded to substantially improve the pre and postoperative diagnosis and risk stratification of thyroid tumors, the morphological examination is still central in the daily routine diagnosis of thyroid pathology. Future is the integrated diagnosis of clinical, morphological, molecular and epigenetic features with the help of artificial intelligence algorithms.
Topics: Humans; Thyroid Nodule; Artificial Intelligence; Adenocarcinoma, Follicular; Thyroid Neoplasms; World Health Organization; Retrospective Studies
PubMed: 37975316
DOI: 10.1097/CCO.0000000000001012 -
Pathology Jan 2021It has been 35 years since Professor Thoenes and his colleagues discovered chromophobe renal cell carcinoma (RCC). Since then, our knowledge about this tumour entity has... (Review)
Review
It has been 35 years since Professor Thoenes and his colleagues discovered chromophobe renal cell carcinoma (RCC). Since then, our knowledge about this tumour entity has changed and novel tumour entities have been discovered. The aim of this review is to discuss recent molecular findings and open questions in diagnosing chromophobe-like/oncocytic neoplasms. The broader differential diagnosis of chromophobe-like and oncocytoma-like neoplasms includes SDH-deficient renal cell carcinoma, fumarate hydratase (FH) deficient RCC, epitheloid angiomyolipoma ('oncocytoma like'), MiT family translocation RCC and the emerging entity of eosinophilic solid and cystic renal cell carcinoma. After separation of these tumours from chromophobe RCC, it becomes evident that chromophobe RCC are low malignant tumours with a 5-6% risk of metastasis. Recent next generation sequencing (NGS) and DNA methylation profiling studies have confirmed Thoenes' theory of a distal tubule derived origin of chromophobe RCC and renal oncocytomas. Comprehensive genomic analyses of chromophobe RCC have demonstrated a low somatic mutation rate and identified TP53 and PTEN as the most frequently mutated genes, whereas 'unclassified' RCC with oncocytic or chromophobe-like features can show somatic inactivating mutations of TSC2 or activating mutations of MTOR as the primary molecular alterations. For the future, it would be desirable to create a category of 'oncocytic/chromophobe RCC, NOS' with the potential of further molecular studies for identification of TSC1/2 mutations in these rare tumours.
Topics: Adenoma, Oxyphilic; Carcinoma, Renal Cell; Diagnosis, Differential; Humans; Kidney Neoplasms
PubMed: 33183792
DOI: 10.1016/j.pathol.2020.09.015 -
Cancer Cytopathology Aug 2021The salivary gland neoplasm of unknown malignant potential (SUMP) category reflects the cytomorphologic overlap and complexity of reporting salivary gland cytology in...
Analysis of the risk of malignancy associated with the basaloid and oncocytic subtypes of the salivary gland neoplasm of unknown malignant potential (SUMP) category in the Milan system.
BACKGROUND
The salivary gland neoplasm of unknown malignant potential (SUMP) category reflects the cytomorphologic overlap and complexity of reporting salivary gland cytology in the Milan system. It includes neoplasms for which a diagnosis of a specific entity cannot be made and, more importantly, for which a carcinoma cannot be entirely excluded. For risk stratification, the subcategorization of SUMP based on the predominant cell type is recommended. This study was aimed at evaluating the risk of neoplasm (RON) and the risk of malignancy (ROM) of the basaloid and oncocytic subtypes of the SUMP category.
METHODS
A retrospective analysis of 482 salivary gland fine-needle aspirations from 2012 to 2019 resulted in 48 SUMP cases. The cytology of these cases was reviewed and reclassified as the basaloid or oncocytic subtype. Surgical follow-up was available for 36 cases. The RON and ROM for each subtype were calculated.
RESULTS
The RON and ROM were 100% and 23%, respectively, for monomorphic basaloid tumors and 88% and 58.8%, respectively, for monomorphic oncocytic tumors. The ROM for basaloid tumors was 8.3% without matrix/with minimal matrix and 60% with an nonfibrillary matrix. The ROM for oncocytic tumors was 50% without a cystic background and 60% with a cystic or mucinous background. The difference was not statistically significant for either of the subgroups.
CONCLUSIONS
Even though statistically not significant in our study, the differential ROMs within the oncocytic and basaloid subgroups help in the risk stratification of SUMP cases. Further subcategorization based on the stroma and background helps in limiting the differential diagnosis but does not necessarily add to the value of the risk stratification.
Topics: Biopsy, Fine-Needle; Humans; Oxyphil Cells; Retrospective Studies; Salivary Gland Neoplasms; Salivary Glands
PubMed: 33788998
DOI: 10.1002/cncy.22427 -
World Journal of Gastroenterology Dec 2013Intraductal papillary neoplasm of the bile duct (IPNB) is a variant of bile duct carcinoma that is characterized by intraductal growth and better outcomes compared with... (Review)
Review
Intraductal papillary neoplasm of the bile duct (IPNB) is a variant of bile duct carcinoma that is characterized by intraductal growth and better outcomes compared with common cholangiocarcinoma. IPNBs are mainly found in patients from Far Eastern areas, where hepatolithiasis and clonorchiasis are endemic. According to the immunohistochemical profiles of the mucin core proteins, IPNBs are classified into four types: pancreaticobiliary, intestinal, gastric, and oncocytic. Approximately 40%-80% of IPNBs contain a component of invasive carcinoma or tubular or mucinous adenocarcinoma, suggesting that IPNB is a disease with high potential for malignancy. It is difficult to make an accurate preoperative diagnosis because of IPNB's low incidence and the lack of specificity in its clinical manifestation. The most common abnormal preoperative imaging findings of IPNB are intraductal masses and the involvement of bile duct dilation. Simultaneous proximal and distal bile duct dilation can be detected in some cases, which has diagnostic significance. Cholangiography and cholangioscopy are needed to confirm the pathology and demonstrate the extent of the lesions. However, pathologic diagnosis by biopsy cannot reflect the actual stage in many cases because different foci may be of different stages and because mixed pathologic findings may exist in the same lesion. Surgical resection is the major treatment. Systematic cholangioscopy with staged biopsies and frozen sections is recommended during resection to ensure that no minor tumors are left and that curative resection is achieved. Staging, histologic subtype, curative resection and lymph node metastasis are factors affecting long-term survival.
Topics: Adenocarcinoma, Mucinous; Bile Duct Neoplasms; Bile Ducts; Biliary Tract Surgical Procedures; Biomarkers, Tumor; Biopsy; Carcinoma, Papillary; Diagnosis, Differential; Diagnostic Imaging; Dilatation, Pathologic; Endoscopy, Digestive System; Humans; Neoplasm Invasiveness; Neoplasm Staging; Papilloma; Predictive Value of Tests; Risk Factors; Treatment Outcome
PubMed: 24379576
DOI: 10.3748/wjg.v19.i46.8595 -
Frontiers in Endocrinology 2021The main objective of this study was to review the clinicopathologic characteristics and outcome of patients with oncocytic papillary thyroid carcinoma (PTC) and...
Oncocytic Papillary Thyroid Carcinoma and Oncocytic Poorly Differentiated Thyroid Carcinoma: Clinical Features, Uptake, and Response to Radioactive Iodine Therapy, and Outcome.
OBJECTIVE
The main objective of this study was to review the clinicopathologic characteristics and outcome of patients with oncocytic papillary thyroid carcinoma (PTC) and oncocytic poorly differentiated thyroid carcinoma (PDTC). The secondary objective was to evaluate the prevalence and outcomes of RAI use in this population.
METHODS
Patients with oncocytic PTC and PDTC who were treated at a quaternary cancer centre between 2002 and 2017 were retrospectively identified from an institutional database. All patients had an expert pathology review to ensure consistent reporting and definition. The cumulative incidence function was used to analyse locoregional failure (LRF) and distant metastasis (DM) rates. Univariable analysis (UVA) was used to assess clinical predictors of outcome.
RESULTS
In total, 263 patients were included (PTC [n=218], PDTC [n=45]) with a median follow up of 4.4 years (range: 0 = 26.7 years). Patients with oncocytic PTC had a 5/10-year incidence of LRF and DM, respectively, of 2.7%/5.6% and 3.4%/4.5%. On UVA, there was an increased risk of DM in PTC tumors with widely invasive growth (HR 17.1; p<0.001), extra-thyroidal extension (HR 24.95; p<0.001), angioinvasion (HR 32.58; p=0.002), focal dedifferentiation (HR 19.57, p<0.001), and focal hobnail cell change (HR 8.67, p=0.042). There was additionally an increased risk of DM seen in male PTC patients (HR 5.5, p=0.03).The use of RAI was more common in patients with larger tumors, angioinvasion, and widely invasive disease. RAI was also used in the management of DM and 43% of patients with oncocytic PTC had RAI-avid metastatic disease. Patients with oncocytic PDTC had a higher rate of 5/10-year incidence of LRF and DM (21.4%/45.4%; 11.4%/40.4%, respectively). Patients with extra-thyroidal extension had an increased risk of DM (HR 5.52, p=0.023) as did those with angioinvasion. Of the patients with oncocytic PDTC who received RAI for the treatment of DM, 40% had RAI-avid disease.
CONCLUSION
We present a large homogenous cohort of patients with oncocytic PTC and PDTC, with consistent pathologic reporting and definition. Patients with oncocytic PTC have excellent clinical outcomes and similar risk factors for recurrence as their non-oncocytic counterparts (angioinvasion, large tumor size, extra-thyroidal extension, and focal dedifferentiation). Compared with oncocytic PTCs, the adverse biology of oncocytic PDTCs is supported with increased frequency of DM and lower uptake of RAI.
Topics: Adenoma, Oxyphilic; Adult; Aged; Aged, 80 and over; Cohort Studies; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Retrospective Studies; Thyroid Cancer, Papillary; Thyroid Neoplasms; Thyroidectomy; Treatment Outcome
PubMed: 34975765
DOI: 10.3389/fendo.2021.795184 -
Endocrine-related Cancer Nov 2023Molecular testing contributes to improving the diagnosis of indeterminate thyroid nodules (ITNs). ThyroidPrint® is a ten-gene classifier aimed to rule out malignancy in...
Molecular testing contributes to improving the diagnosis of indeterminate thyroid nodules (ITNs). ThyroidPrint® is a ten-gene classifier aimed to rule out malignancy in ITN. Post-validation studies are necessary to determine the real-world clinical benefit of ThyroidPrint® in patients with ITN. A single-center, prospective, noninterventional clinical utility study was performed, analyzing the impact of ThyroidPrint® in the physicians' clinical decisions for ITN. Demographics, nodule characteristics, benign call rates (BCRs), and surgical outcomes were measured. Histopathological data were collected from surgical biopsies of resected nodules. Of 1272 fine-needle aspirations, 109 (8.6%) were Bethesda III and 135 (10.6%) were Bethesda IV. Molecular testing was performed in 155 of 244 ITN (63.5%), of which 104 were classified as benign (BCR of 67.1%). After a median follow-up of 15 months, 103 of 104 (99.0%) patients with a benign ThyroidPrint® remained under surveillance and one patient underwent surgery which was a follicular adenoma. Surgery was performed in all 51 patients with a suspicious for malignancy as per ThyroidPrint® result and in 56 patients who did not undergo testing, with a rate of malignancy of 70.6% and 32.1%, respectively. A higher BCR was observed in follicular lesion of undetermined significance (87%) compared to atypia of undetermined significance (58%) (P < 0.05). False-positive cases included four benign follicular nodules and six follicular and four oncocytic adenomas. Our results show that, physicians chose active surveillance instead of diagnostic surgery in all patients with a benign ThyroidPrint® result, reducing the need for diagnostic surgery in 67% of patients with preoperative diagnosis of ITN.
Topics: Humans; Prospective Studies; Gene Expression Profiling; Retrospective Studies; Thyroid Neoplasms; Thyroid Nodule; Biopsy, Fine-Needle
PubMed: 37671897
DOI: 10.1530/ERC-22-0409