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JAMA Otolaryngology-- Head & Neck... Mar 2024Oncocytic (Hürthle cell) thyroid carcinoma is a follicular cell-derived neoplasm that accounts for approximately 5% of all thyroid cancers. Until recently, it was... (Review)
Review
IMPORTANCE
Oncocytic (Hürthle cell) thyroid carcinoma is a follicular cell-derived neoplasm that accounts for approximately 5% of all thyroid cancers. Until recently, it was categorized as a follicular thyroid carcinoma, and its management was standardized with that of other differentiated thyroid carcinomas. In 2022, given an improved understanding of the unique molecular profile and clinical behavior of oncocytic thyroid carcinoma, the World Health Organization reclassified oncocytic thyroid carcinoma as distinct from follicular thyroid carcinoma. The International Thyroid Oncology Group and the American Head and Neck Society then collaborated to review the existing evidence on oncocytic thyroid carcinoma, from diagnosis through clinical management and follow-up surveillance.
OBSERVATIONS
Given that oncocytic thyroid carcinoma was previously classified as a subtype of follicular thyroid carcinoma, it was clinically studied in that context. However, due to its low prevalence and previous classification schema, there are few studies that have specifically evaluated oncocytic thyroid carcinoma. Recent data indicate that oncocytic thyroid carcinoma is a distinct class of malignant thyroid tumor with a group of distinct genetic alterations and clinicopathologic features. Oncocytic thyroid carcinoma displays higher rates of somatic gene variants and genomic chromosomal loss of heterozygosity than do other thyroid cancers, and it harbors unique mitochondrial DNA variations. Clinically, oncocytic thyroid carcinoma is more likely to have locoregional (lymph node) metastases than is follicular thyroid carcinoma-with which it was formerly classified-and it develops distant metastases more frequently than papillary thyroid carcinoma. In addition, oncocytic thyroid carcinoma rarely absorbs radioiodine.
CONCLUSIONS AND RELEVANCE
The findings of this review suggest that the distinct clinical presentation of oncocytic thyroid carcinoma, including its metastatic behavior and its reduced avidity to radioiodine therapy, warrants a tailored disease management approach. The reclassification of oncocytic thyroid carcinoma by the World Health Organization is an important milestone toward developing a specific and comprehensive clinical management for oncocytic thyroid carcinoma that considers its distinct characteristics.
Topics: Humans; Iodine Radioisotopes; Thyroid Neoplasms; Adenoma, Oxyphilic; Adenocarcinoma, Follicular; Lymphatic Metastasis
PubMed: 38206595
DOI: 10.1001/jamaoto.2023.4323 -
Cancer Discovery Aug 2023A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many...
UNLABELLED
A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that Hürthle cell carcinoma of the thyroid (HTC) models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in glucose metabolism. CRISPR-Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I-mutant HTC cells. We demonstrate in cultured cells and a patient-derived xenograft model that small-molecule inhibitors of lactate dehydrogenase selectively induce an ATP crisis and cell death in HTC. This work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration.
SIGNIFICANCE
HTC is enriched in somatic mtDNA mutations predicted to affect complex I of the electron transport chain (ETC). We demonstrate that these mutations impair respiration and induce a therapeutically tractable reliance on aerobic fermentation for cell survival. This work provides a rationale for targeting fermentation in cancers harboring irreversible genetically encoded ETC defects. See related article by Gopal et al., p. 1904. This article is highlighted in the In This Issue feature, p. 1749.
Topics: Humans; Fermentation; Thyroid Neoplasms; Adenoma, Oxyphilic; DNA, Mitochondrial; Adenocarcinoma; Carcinoma
PubMed: 37262072
DOI: 10.1158/2159-8290.CD-22-0982 -
Cancer Cytopathology Sep 2023ThyroSeq molecular testing assesses the probability of malignancy (POM) in thyroid fine-needle aspiration cytology (FNAC) with indeterminate cytology. The aim was to...
BACKGROUND
ThyroSeq molecular testing assesses the probability of malignancy (POM) in thyroid fine-needle aspiration cytology (FNAC) with indeterminate cytology. The aim was to investigate whether Bethesda category IV (BIV) subcategories are associated with specific molecular alterations, molecular-derived risk of malignancy (MDROM), and risk of malignancy (ROM).
METHODS
FNAC slides, associated ThyroSeq, version 3, Genomic Classifier results, and surgical follow-up were retrieved for BIV nodules. Nodules were subcategorized as follicular neoplasm (FN) with or without cytologic atypia or oncocytic follicular neoplasm (OFN). The MDROM, ROM, and frequency of molecular alterations in FN and OFN were analyzed. p < .05 was considered significant.
RESULTS
A total of 92 FNAC were identified and subcategorized into 46 FN (15 with and 31 without cytologic atypia) and 46 OFN. The benign call rate and the positive call rate were 49% and 51%, respectively. The MDROM in BIV was 34.3%, trending lower in OFN than in FN. RAS mutations were significantly more frequent in FN when compared to OFN (p = .02). Chromosomal copy number alterations were more often present in OFN than in FN (p < .01). On histologic follow-up, ROM in OFN was trending lower than in FN (p = .1). The most common diagnosis in OFN was oncocytic adenoma, whereas follicular variant papillary thyroid carcinoma was most common in FN.
CONCLUSIONS
The MDROM and ROM were trending lower in OFN compared with FN, and the molecular alterations differed between OFN and FN subcategories.
Topics: Humans; Thyroid Neoplasms; Adenoma, Oxyphilic; Genomics; Molecular Diagnostic Techniques; Probability; Thyroid Nodule; Adenocarcinoma, Follicular; Retrospective Studies
PubMed: 37358081
DOI: 10.1002/cncy.22737 -
Mayo Clinic Proceedings Mar 2024
Topics: Humans; Adenoma, Oxyphilic; Thyroid Neoplasms
PubMed: 38432755
DOI: 10.1016/j.mayocp.2023.11.002 -
Endokrynologia Polska 2024Not required for Clinical Vignettes.
Not required for Clinical Vignettes.
Topics: Humans; Adenoma, Oxyphilic; Adrenal Gland Neoplasms; Female; Male; Middle Aged; Adrenal Glands
PubMed: 38646992
DOI: 10.5603/ep.99035 -
Surgery Jan 2024Of the half a million cases of thyroid cancer diagnosed annually, 95% are differentiated thyroid cancers. Although clinical guidelines recommend surgical resection...
BACKGROUND
Of the half a million cases of thyroid cancer diagnosed annually, 95% are differentiated thyroid cancers. Although clinical guidelines recommend surgical resection followed by radioactive iodine ablation, loss of sodium-iodine symporter expression causes up to 20% of differentiated thyroid cancers to become radioactive iodine refractory. For patients with radioactive iodine refractory disease, there is an urgent need for new diagnostic and therapeutic approaches. We evaluated the thyroid-stimulating hormone receptor as a potential target for imaging of differentiated thyroid cancer.
METHODS
We immunostained tissue microarrays containing 52 Hurthle cell carcinomas to confirm thyroid-stimulating hormone receptor expression. We radiolabeled chelator deferoxamine conjugated to recombinant human thyroid-stimulating hormone analog superagonist TR1402 with Zr (t = 78.4 h, β =22.7%) to produce [Zr]Zr-TR1402. We performed in vitro uptake assays in high-thyroid-stimulating hormone receptor and low-thyroid-stimulating hormone receptor-expressing THJ529T and FTC133 thyroid cancer cell lines. We performed in vivo positron emission tomography/computed tomography and biodistribution studies in male athymic nude mice bearing thyroid-stimulating hormone receptor-positive THJ529T tumors.
RESULTS
Immunohistochemical analysis revealed 62% of patients (27 primary and 5 recurrent) were thyroid-stimulating hormone receptor membranous immunostain positive. In vitro uptake of 1nM [Zr]Zr-TR1402 was 38 ± 17% bound/mg in thyroid-stimulating hormone receptor-positive THJ529T thyroid cancer cell lines compared to 3.2 ± 0.5 in the low-expressing cell line (P < .01), with a similar difference seen in FTC133 cell lines (P < .0001). In vivo and biodistribution studies showed uptake of [Zr]Zr-TR1402 in thyroid-stimulating hormone receptor-expressing tumors, with a mean percentage of injected dose/g of 1.9 ± 0.4 at 3 days post-injection.
CONCLUSION
Our observation of thyroid-stimulating hormone receptor expression in tissue microarrays and [Zr]Zr-TR1402 accumulation in thyroid-stimulating hormone receptor-positive thyroid cancer cells and tumors suggests thyroid-stimulating hormone receptor is a promising target for imaging of differentiated thyroid cancer.
Topics: Animals; Humans; Male; Mice; Cell Line, Tumor; Iodine; Iodine Radioisotopes; Mice, Nude; Positron-Emission Tomography; Receptors, Thyrotropin; Thyroid Neoplasms; Thyrotropin; Tissue Distribution; Adenoma, Oxyphilic
PubMed: 37919223
DOI: 10.1016/j.surg.2023.05.045 -
Endocrine Pathology Sep 2023Progress in the field of pediatric thyroid pathology has linked DICER1 mutations to benign follicular cell-derived thyroid tumors (e.g., follicular adenoma with...
Progress in the field of pediatric thyroid pathology has linked DICER1 mutations to benign follicular cell-derived thyroid tumors (e.g., follicular adenoma with papillary architecture, follicular nodular disease), low-risk follicular cell-derived differentiated thyroid carcinomas and PDTCs enriched in fatal or recurrent/progressive disease. The dismal outcome of DICER1-harboring pediatric PDTCs stems from a limited number of reported patients' data given the rarity of pediatric PDTCs. In light of the former observations, the current study assessed clinicopathological variables of a series of 5 pediatric (≤ 18 years old) PDTCs using the Turin criteria (WHO 2022) and also examined the status of DICER1 and TERT promoter mutations. Five PDTCs (3 males, 2 females) were included in the study. The mean age at the time of diagnosis was 15.4 years. No patients had a history of DICER1 syndrome-related tumors or other clinicopathological diagnostic features of DICER1 syndrome. The mean tumor size was 3.9 cm. All tumors were completely submitted for microscopic examination. There was increased mitotic activity ranging from 3 to 10 mitoses per 2 mm. Tumor necrosis was present in two cases. No PDTC harbored TERT promoter mutation. DICER1 hot spot mutation was identified in one (20%) tumor. The DICER1-mutant tumor had neither associated differentiated thyroid carcinoma component nor other pathological findings in the adjacent thyroid parenchyma. The DICER1-mutant PDTC showed widely invasive growth confined to the thyroid parenchyma. Despite the widely invasive growth, the tumor lacked vascular invasion. Two DICER1 wild-type PDTCs had lymphocytic thyroiditis and another one had underlying follicular nodular disease and/or follicular adenomas. Three DICER1 wild-type PDTCs also had an associated differentiated thyroid carcinoma component with no high-grade features. No abnormal p53 expression (overexpression or global loss) was recorded in all tested tumors. Four patients had follow-up data with a mean follow-up time of 60.25 months (range: 18-86 months). One patient with no evidence of disease recurrence died of an unrelated cause after 18 months of the initial surgery, all remaining patients were alive with no distant metastasis at their last visit. Of the 4 patients with lymph node (LN) dissection, one DICER1 wild-type PDTC had recurrent nodal disease. During the follow-up period (72 months), no local recurrence or distant metastases was detected in the DICER1-mutant PDTC. Taken together all reported findings from earlier series, DICER1 mutations alone may not necessarily indicate dismal outcome in a subset of pediatric PDTCs. The occurrence of additional genomic alterations as discussed in some earlier reports may be contributing to tumor progression or aggressivity of pediatric PDTCs. The lack of vascular invasion in the current DICER1-mutant pediatric PDTC may also explain an indolent biologic outcome. The risk escalation of DICER1 mutations should integrate the status of additional genetic events and well-established pathologic variables in order to ensure predictive dynamic risk stratification in DICER1-mutant pediatric PDTCs. Additional studies are needed to corroborate the findings of this study and advance our knowledge in pediatric thyroid neoplasia.
Topics: Male; Female; Humans; Child; Adolescent; Thyroid Neoplasms; Prognosis; Adenocarcinoma; Adenoma, Oxyphilic; Mutation; Adenocarcinoma, Follicular; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 37574466
DOI: 10.1007/s12022-023-09780-2 -
Head and Neck Pathology Mar 2024Oncocytoid salivary tumors include several entities such as oncocytoma, Warthin tumor, secretory carcinoma (SC), salivary duct carcinoma (SDC), acinic cell carcinoma... (Review)
Review
BACKGROUND
Oncocytoid salivary tumors include several entities such as oncocytoma, Warthin tumor, secretory carcinoma (SC), salivary duct carcinoma (SDC), acinic cell carcinoma (AciCC), oncocytic mucoepidermoid carcinoma (OMEC), intraductal carcinoma, and epithelial myoepithelial carcinoma (EMC). This review investigates the differential diagnosis of oncocytoid salivary tumors and explore the role of newly described immunostains as valuable tools for their diagnosing and potentially guiding treatment options.
METHODS
We assess the utility of incorporating new immunohistochemical markers in routine practice to aid in diagnosing oncocytoid salivary tumors and potentially provide treatment options.
RESULTS
In SDC, AR and Her2 immunostains are utilized as diagnostic tools and biomarkers for selecting patients who might benefit from Androgen-deprivation therapy (ADT) and HER2-targeted therapy. Furthermore, nuclear Pan-Trk immunostaining can aid in diagnosing SC. Additionally, NR4A3 immunostaining has been shown high sensitivity and specificity in identifying AciCC in both surgical and cytologic specimens. Similarly, RAS Q61R mutant-specific immunostaining, detected in EMC, may offer a cost-effective diagnostic marker for this tumor. Although further studies are required to evaluate the role of BSND, this marker has been reported to be positive in Warthin tumor and oncocytoma, aiding in differentiating them from other oncocytoid tumors, particularly OMEC. In addition, BRAFV600E mutant-specific immunostaining can serve as a diagnostic and potentially therapeutic marker for oncocytic intraductal carcinoma in mutation positive cases.
CONCLUSION
Oncocytoid salivary tumors may have overlapping morphologies, posing diagnostic challenges for pathologists. Recently described immunohistochemical markers may offer valuable tools for diagnosing and potentially guiding treatment options for these tumors.
Topics: Male; Humans; Adenoma, Oxyphilic; Adenolymphoma; Immunohistochemistry; Diagnosis, Differential; Carcinoma, Intraductal, Noninfiltrating; Androgen Antagonists; Biomarkers, Tumor; Prostatic Neoplasms; Salivary Gland Neoplasms; Carcinoma, Acinar Cell; Carcinoma, Ductal; Breast Neoplasms; Carcinoma
PubMed: 38502259
DOI: 10.1007/s12105-024-01622-9 -
The Journal of Urology Sep 2023Technetium-99m-sestamibi single-photon emission CT/x-ray CT is an emerging clinical tool to differentiate oncocytic tumors from renal cell carcinomas. We report data...
PURPOSE
Technetium-99m-sestamibi single-photon emission CT/x-ray CT is an emerging clinical tool to differentiate oncocytic tumors from renal cell carcinomas. We report data from a large institutional cohort of patients who underwent technetium-99m-sestamibi scans during evaluation of renal masses.
MATERIALS AND METHODS
Patients who underwent technetium-99m-sestamibi single-photon emission CT/x-ray CT between February 2020 and December 2021 were included in the analysis. Scans were defined as "hot" for oncocytic tumor when technetium-99m-sestamibi uptake was qualitatively equivalent or higher between the mass of interest and normal renal parenchyma, suggesting oncocytoma, hybrid oncocytic/chromophobe tumor, or chromophobe renal cell carcinoma. Demographic, pathological, and management strategy data were compared between "hot" and "cold" scans. For individuals who underwent diagnostic biopsy or extirpative procedures, the concordance between radiological findings and pathology was indexed.
RESULTS
A total of 71 patients (with 88 masses) underwent technetium-99m-sestamibi imaging with 60 (84.5%) patients having at least 1 "cold" mass on imaging and 11 (15.5%) patients exhibiting only "hot" masses. Pathology was available for 7 "hot" masses, with 1 biopsy specimen (14.3%) being discordant (clear cell renal cell carcinoma). Five patients with "cold" masses underwent biopsy. Out of 5 biopsied masses, 4 (80%) were discordant oncocytomas. Of the extirpated specimens, 35/40 (87.5%) harbored renal cell carcinoma and 5/40 (12.5%) yielded discordant oncocytomas. In sum, 20% of pathologically sampled masses that were "cold" on technetium-99m-sestamibi imaging still harbored oncocytoma/hybrid oncocytic/chromophobe tumor/chromophobe renal cell carcinoma.
CONCLUSIONS
Further work is needed to define utility of technetium-99m-sestamibi in real-world clinical practice. Our data suggest this imaging strategy is not yet ready to replace biopsy.
Topics: Humans; Carcinoma, Renal Cell; Technetium Tc 99m Sestamibi; Kidney Neoplasms; Adenoma, Oxyphilic; Single Photon Emission Computed Tomography Computed Tomography; Tomography, X-Ray Computed; Tomography, Emission-Computed, Single-Photon; Radiopharmaceuticals
PubMed: 37378576
DOI: 10.1097/JU.0000000000003557 -
Neuro-oncology Aug 2023"Primary papillary epithelial tumor of the sella (PPETS)" is a recently described rare tumor entity of the central nervous system (CNS) with stereotypic location in the...
BACKGROUND
"Primary papillary epithelial tumor of the sella (PPETS)" is a recently described rare tumor entity of the central nervous system (CNS) with stereotypic location in the sella. Comprehensive molecular investigations and epigenetic profiles of PPETS have not been performed to date.
METHODS
We report a comprehensive clinical, histopathologic, and molecular assessment of 5 PPETS cases in comparison with a cohort composed of 7 choroid plexus papilloma (CPP), 7 central neurocytoma (CN), 15 posterior pituitary tumor (PPT) including 4 pituicytoma, 6 granular cell tumors of the sellar region (GCT), and 5 spindle cell oncocytoma.
RESULTS
All PPETS had good outcomes. Immunohistochemically, PPETS tumors showed positive staining with TTF1, EMA, AE1/AE3, MAP2, and Vimentin, but were negatively stained with Syn, GFAP, CgA, and S100, and sporadically stained with Ki-67. In unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analyses of DNA-methylation data, PPETS and PPT tumors formed a distinct cluster irrespective of their histologic types. However, PPETS tumors did not cluster together with CPP and CN samples. Similar findings were obtained when our samples were projected into the reference cohort of the brain tumor classifier. Substantial fractions of the PPETS and PPT tumors shared broadly similar chromosomal copy number alterations. No mutations were detected using targeted next-generation sequencing.
CONCLUSIONS
Though more cases are needed to further elucidate the molecular pathogenesis of these tumors, our findings indicate that PPETS and PPT tumors may constitute a single neurooncological entity.
Topics: Humans; Pituitary Neoplasms; Neoplasms, Glandular and Epithelial; Adenoma, Oxyphilic; DNA Methylation; Central Nervous System
PubMed: 37058118
DOI: 10.1093/neuonc/noad067