Oncocytoma Research Articles

Reappraisal of Oncocytic Adenocarcinoma: Unveiling Its Connection to Oncocytic Variants of Salivary Duct Carcinoma and Mucoepidermoid Carcinoma Through ImmunoHisto-Molecular Perspectives.

Oncocytic adenocarcinoma (OC) of the salivary glands is a rare and controversial entity. It was recently reclassified as "salivary carcinoma NOS and emerging entities" in the 2022 WHO classification of head and neck tumors. The lack of specific molecular alterations and its potential affiliation with other salivary gland carcinomas, such as the oncocytic mucoepidermoid carcinomas (OMEC) or the oncocytic subtype of salivary duct carcinomas (OSDC) justified this reclassification. It is becoming essential to clarify the complex spectrum of potential diagnoses surrounding oncocytic tumors. The objective of this study was to explore the histologic features, as well as the immunohistochemical and molecular profiles, of cases previously diagnosed as OC or OMEC of the salivary glands. This study involved 28 cases of carcinomas with a predominantly oncocytic component. The sex distribution was equal. The median age was 59 years (range 10 to 89). Most of these cases originated from the parotid gland (25/28). The mean tumor size was 2.4cm (range 0.5 to 6.5). Primary immuno-morphological and mutation/gene fusion profiles reclassified mainly (64.3%, 18/28). Most of them were reclassified in descending order as OSDC (8/18), OMEC (5/18), and OC (2/18). But 3 cases remained unclassified (3/18). The transcriptomic analysis found a proximity of their transcriptomic profile with the OMEC group and a distance from the OSDCs. These findings imply that OC is not distinct but represents oncocytic variants of other salivary carcinomas. It underscores the importance of thorough morphologic, immunohistochemical, and molecular examinations to accurately diagnose carcinomas with predominant oncocytic components in the salivary glands.

Mitochondrial Proteome Defined Molecular Pathological Characteristics of Oncocytic Thyroid Tumors.

Oncocytic thyroid tumors are characterized by an elevated mitochondrial density within the cells, distinguishing them from other thyroid tumors, exhibit distinct clinical behaviors, including increased invasiveness and iodine therapy resistance. However, the proteomic alterations in oncocytic thyroid tumors remain inadequately characterized. In this study, we analyzed 156 Asian patients with oncocytic thyroid adenomas (OA) and carcinomas (OCA) to explore their clinical, genetic, and proteomic features. Genetic testing of 73 samples revealed frequent mutations in TERT, NRAS, EIF1AX, EZH1, and HRAS, with TERT promoter mutations being exclusive to OCAs. Proteomic analysis identified 66 mitochondrial-specific proteins significantly highly expressed in oncocytic tumors than in non-oncocytic tumors. This led to the development of a thyroid oncocytic score (TOS) to quantify oncocytic characteristics. Among these proteins, isocitrate dehydrogenase 2 (IDH2) was substantially overexpressed in oncocytic tumors and further confirmed by immunohistochemistry in oncocytic tumor slides (n = 41) and non-oncocytic tumor slides (n = 40). Moreover, IDH2 is significantly overexpressed in OCA compared to OA highlighting its potential as a biomarker for differential diagnosis of oncocytic tumors and malignancy. These findings improve the understanding of oncocytic thyroid tumors molecular pathology and suggest IDH2 as a valuable marker for clinical management.

Targeted Therapy in Salivary Gland Cancer: Prevalence of a Selected Panel of Actionable Molecular Alterations in a German Tertiary Referral Center Patient Cohort.

Salivary gland carcinomas (SGC) are a heterogeneous group of malignancies, with 24 subtypes defined by the World Health Organization (WHO). The standard of therapy is surgical resection, with adjuvant radiotherapy in most cases. However, disease recurrence (R) or metastasis (M) is common and no active systemic therapies are currently available for RM-SGC resulting in a 5-year survival rate of only 20%. Overall, 55 SGC patients with seven different histological tumor subtypes were included in this study. formalin-fixed paraffin-embedded (FFPE) tissue samples were used for immunohistochemical (IHC) staining targeting HER2/neu, androgen receptor (AR), PD-L1, EGFR, panTRK, and TROP2. Fluorescence in situ hybridization (FISH) was performed for detecting HER2/neu amplifications and NTRK1/2/3 translocations in selected cases with relevant HER2/neu and panTRK protein expression, respectively. IHC and FISH results were correlated with patients' clinical and histopathological data. The overall prevalence of druggable molecular alterations, defined as an immunoreactive score ≥ 9 in at least one of the analyzed targets, was 54.4% with the highest percentage in oncocytic carcinomas (100%) and lowest percentage in acinic cell carcinomas (10%). EGFR overexpression proved to be the most common alteration (32.7% of cases) followed by overexpression of TROP2 (27.3%), AR (10.9%), HER2/neu (7.3%), PD-L1 (1.8%), and panTRK (1.8%). HER2/neu amplifications were found in 50% and NTRK translocations were found in 100% of all cases with elevated Her2/neu and panTRK protein expression, respectively. Our data indicate that targeted therapy using e.g., trastuzumab deruxtecan, bicalutamide, pembrolizumab, cetuximab, entrectinib or sacituzumab govitecan might be a promising option especially for a relevant subset of patients with RM-SGC not suitable for salvage surgery. However, evidence from clinical studies regarding response rates to these therapies remains sparse, which underlines the need of multicenter clinical trials.

Clinically aggressive follicular cell-derived thyroid carcinoma: A comprehensive series with histomolecular characterization and discovery of novel gene fusions

Thyroid cancer rates are increasing, mostly with a good prognosis and less than 2 % of cases are more aggressive. Recent efforts focus on understanding molecular events predicting tumor aggressiveness and treatment targets in advanced thyroid cancer. This study concerned 57 patients with aggressive metastatic, and/or radioiodine-refractory thyroid carcinomas, excluding anaplastic cases. Molecular profiling, including next-generation sequencing and RNA sequencing, was conducted to dissect the complex molecular landscape of these aggressive tumors. Histopathological analysis indicated that papillary carcinomas and high-grade thyroid carcinomas were predominant. The molecular analysis revealed a spectrum of mutations, with prevalent occurrences of BRAF V600E, TERT promoter, and RAS mutations. RNA sequencing identified ten gene fusions, such as NTRK and RET fusions. Three novel fusions were discovered: UGGT1::TERT, BTBD9::TERT, and TG::IGF1R, potentially driving aggressive behavior. UGGT1::TERT was linked to radioiodine-refractory tall cell PTC, BTBD9::TERT to high-grade follicular PTC, and TG::IGF1R to oncocytic carcinoma. These findings underscore the importance of TERT alterations in aggressive phenotypes and offer insights into molecular mechanisms guiding targeted therapies. Further research is necessary to confirm their significance as diagnostic and prognostic markers in thyroid cancer.

Pemetrexed-carboplatin salvage therapy in advanced thyroid cancers.

The overall survival of patients with advanced thyroid cancers that have progressed following targeted therapies is limited, indicating a strong need for salvage treatments. We retrospectively analyzed patients with refractory advanced thyroid cancer treated with pemetrexed-carboplatin (PC) at Mayo Clinic since 2019. Eleven patients, three with anaplastic thyroid cancer (ATC), seven with differentiated or poorly differentiated thyroid cancer (DTC), and one with oncocytic carcinoma of the thyroid, were treated with novel salvage PC. Patients with DTC (n = 7) had durable responses with a median progression-free survival of 29 months. One responder included a patient with ATC whose disease progressed following pembrolizumab/axitinib, lenvatinib, and dabrafenib/trametinib. On this fourth line treatment, the patient remains on therapy to date, over 12 months after initial response. This case series reinforces prior published phase I clinical trial data and shows that pemetrexed can have potent efficacy in the treatment of the most advanced thyroid cancers.

Dual Immune Checkpoint Inhibition in Patients With Aggressive Thyroid Carcinoma

Aggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition. To evaluate the efficacy of anti-programmed cell death 1 nivolumab and anti-cytotoxic lymphocyte-associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma. This phase 2 nonrandomized clinical trial enrolled patients with RAIR DTC in a single center from October 2017 to May 2019, with exploratory cohorts in MTC and ATC. The data were analyzed between June 2021 and September 2023. Intravenous nivolumab, 3 mg/kg, every 2 weeks and ipilimumab, 1 mg/kg, every 6 weeks until disease progression, intolerable adverse events, or a maximum duration of 2 years. The primary end point of the study was objective response rate (ORR) in RAIR DTC, which was scored according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1. Key secondary end points included safety, progression-free survival, overall survival, and biomarker analyses. A total of 51 patients were registered, and 49 patients were evaluable for analysis. The median (range) age was 65 years (30-88 years), and 25 participants (51%) were female. ORR in the DTC cohort was 9.4% (3/32 [95% CI, 2.8%-28.5%]), with all partial responses in either oncocytic carcinoma (2/6 [33.0%]) or poorly differentiated thyroid carcinoma (1/5 [20.0%]). Clinical benefit rates were 62.5% (20/32) in the overall DTC cohort, including 83.3% (5/6) in oncocytic carcinoma and 40% (2/5) in poorly differentiated thyroid carcinoma. ORR in the exploratory ATC cohort was 30.0% (3/10 [95% CI, 6.7%-65.2%]), with a clinical benefit rates of 50.0% (5/10). No responses were observed in the exploratory MTC cohort. The safety profile was similar to prior reports with dual immune checkpoint inhibition (pruritus, rash, diarrhea, fatigue, and elevation of lipase and liver enzymes). The presence of NRAS tumor genetic sequence variations, but not BRAF V600E, was associated with worse outcomes. This phase 2 nonrandomized clinical trial reported clinical activity of dual immune checkpoint inhibition in aggressive thyroid cancer. The study did not meet its end point in the primary population of RAIR DTC and does not support further investigation in non-biomarker-selected DTC. However, the signal observed in ATC may merit further evaluation. ClinicalTrials.gov Identifier: NCT03246958.

A Case Series of a Rare Parotid Gland Oncocytic Mucoepidermoid Carcinoma

Abstract Introduction/Objective We analyzed two cases of oncocytic mucoepidermoid carcinoma (OMEC) of the parotid gland which highlight the diagnostic challenges of oncocytic salivary gland neoplasms. OMEC’s are a rare type of salivary gland tumor commonly arising from the parotid gland that can easily be mistaken as benign. Proper pathologic diagnosis of these masses is critical, as it guides therapeutic intervention and has prognostic significance. Methods/Case Report In this case series, two patients were analyzed retrospectively for unilateral parotid masses. Results (if a Case Study enter NA) In a 67-year-old female, an MRI and biopsy were performed. Only a differential diagnosis could be provided, which favored oncocytoma or oncocytic carcinoma. Due to this uncertainty, a complete excision of the mass was performed. Considering the cytomorphology, immunohistochemistry (CK5/6 and P63 in oncocytes), and mucicarmine special stain highlighting scattered mucocytes, the patient was diagnosed with a low- grade OMEC. In our second case, an 80-year-old female, FNA of a posterior left ear mass 1 year prior revealed a low- grade oncocytic proliferation. With the presence of a left parotid mass one year later, additional imaging was performed and showed increased T2 hyperintensity on MRI, which caused concern for the clinicians. A superficial limited parotidectomy was performed and a differential of oncocytoma versus oncocytic variant of mucoepidermoid carcinoma was rendered. Further tumor characterization with fluorescence in situ hybridization (FISH) demonstrated a MAML2 translocation which guided diagnosis of OMEC. Conclusion With approximately 30% of all malignant salivary gland tumors being constituted by mucoepidermoid carcinoma, the ability to accurately diagnose even this rare subtype, oncocytic mucoepidermoid carcinoma, is of significant importance and relevance to pathologists in many practice settings. Herein we demonstrate the utility of H&E morphology, immunohistochemistry, and MAML2 FISH in diagnosing OMEC in the setting of oncocytic salivary gland lesions. Future avenues, including tumor molecular profiling, will aid in elucidating clinicopathologic characteristics of this entity.

Molecular Profiling and Surgical Outcomes in Indeterminate Thyroid Nodules: Experience from a Tertiary Care Center

Abstract Introduction/Objective This study examines molecular results(MR) and surgical follow-up(SFU) of cytologically- indeterminate thyroid nodules. Methods/Case Report Atypia-of-undetermined significance/suspicious-for-follicular-neoplasm cases that underwent Quest/ThyroSeq molecular testing between 2015-2022 were analyzed for MR, SFU and lymph node metastasis(LNM). Results (if a Case Study enter NA) 417 cases(Quest=192, ThyroSeq=225). 59% had SFU. 43% malignancy rate.SFU for Quest(49%): non-neoplastic(NNP)=20%, neoplastic(NP)=80%. MR in these cases:NRAS=48, HRAS=19, BRAF=15, KRAS=8, RET/PTC=3, PAX8=2. SFU: papillary thyroid carcinoma(PTC)=35, non-invasive-follicular-thyroid- papillary-neoplasm with papillary-like nuclear features(NIFTP)=20, thyroid nodular follicular disease(TFND)=18, follicular adenoma(FA)=10, follicular carcinoma(FC)=5, oncocytic carcinoma(OC)=1, lymphocytic thyroiditis(LT)=1. Surgical-molecular correlation(SMC): PTC in 3/3 RET/PTC-mutated, 14/15 BRAF-mutated cases. 1 TFND was BRAF- positive. RAS-mutated category: NIFTP=20,PTC=18,TFND=17,FA=9, OA=5, FC=5, LT=1. In RAS-mutated PTCs, NRAS was most common(n=13), followed by HRAS(n=4) and KRAS(n=1). 2 PAX8-mutated cases showed FA and OC. 9/41 malignant cases, all PTC, had LNM, MR:BRAF=6, HRAS=2, RET/PTC=1.SFU for ThyroSeq(68%): NN=10%, NNP=90%. MR:NRAS=34, copy number alterations(CNAs)=25, HRAS=14, BRAF=13, KRAS=11, gene expression alterations(GEA)=7, THADA+IGF2BP3=7, CNAs Hurthle cell type(HCT)=6, EIF1AX=6, DICER1=4, PAX8- PPARG fusion=4, CNAs+GEA=3, NTRK3=3, TERT=2, RAS+EIF1AX=2, TERT+CNAs=2, EIF1AX=1, EZH1=1, RET/PTC1 fusion=1, ALK=1, BRAF K601E=1,RAS+TERT=1, RAS+TERT+PTEN+EIF1AX=1, TERT+BRAF=1, TERT+EIF1AX=1,TP53+CNAs=1. SFU:PTC=39, NIFTP=31, OA=21, FA=20, papillary microcarcinoma(PMiC)=13, TFND=10, OC=7, LT=6, FC=5, poorly differentiated carcinoma(PdC)=1.10/13 BRAF-mutated cases were PTC, other 3 PMiC. SFU of RAS-mutated cases(n=59):TFND=6, LT=4, NIFTP=19, FA=8, OA=4, PTC=13, PMiC=2, FC=2. RAS mutations in PTC: KRAS=6, HRAS=4, NRAS=3. SFU of CNAs-HCT: OA=3, OC=2, TFND=1. Infrequently detected mutations with SFU of PTC:RET/PTC(1/1), ALK(1/1), RAS+TERT(1/1), TERT+BRAF(1/1), BRAF K601E(1/1), RAS+EIF1AX(1/2). SFU of RAS+TERT+PTEN+EIF1AX:PdC. 11/65 malignant cases, all PTC had LNM:BRAF=5, KRAS=3, CNAs=1, EIF1AX=1, TERT+BRAF=1. Conclusion Substantial proportion of cases with positive MR underwent surgical resection. BRAF-positive and CNAs- HCT correlated with PTC and oncocytic neoplasms, respectively. BRAF-positive PTCs had a higher incidence of LNM compared to wild-type cases(46% vs.18%).

7387 A Rare Case Of Concomitant Intrathyroidal Parathyroid Carcinoma With Osteitis Fibrosa Cystica, Masquerading As Oncocytic Thyroid Carcinoma - A Post-operative Diagnosis

Abstract Disclosure: Y. Koh: None. D.E. Chew: None. T.P. Quek: None. Introduction: Parathyroid carcinoma is a rare form of malignancy. An intrathyroidal location of parathyroid carcinoma further complicates the diagnosis as it may be mistakenly presumed to be of thyroid origin instead. We present a case report of an intrathyroidal parathyroid carcinoma which was diagnosed post-total thyroidectomy. Clinical case: A 72-year-old lady was found to have an intrathyroidal mass after presenting with unintentional weight loss and chronic constipation. Ultrasound of the neck showed a 4.0 x 2.9cm markedly hypoechoic solid mass in the mid-lower right thyroid lobe. Fine needle aspiration of the mass was suspicious for an oncocytic neoplasm. She underwent total thyroidectomy with central neck dissection for concerns of oncocytic thyroid carcinoma. Intraoperatively, a 4cm right hard intrathyroidal nodule invading into the right recurrent laryngeal nerve was observed. All 4 parathyroids were identified and preserved. Post-operatively, routine biochemistry to monitor for hypocalcemia showed hypercalcemia instead. This quickly transitioned into hypocalcemia on post-operative day 4, with biochemistry supportive of hungry bone syndrome [adjusted calcium 2.05mmol/L [normal range (NR) 2.15-2.5], phosphate 0.6mmol/L (NR 0.8-1.4), PTH 8.2pmol/L (NR 0.8-6.8), 25-OH vitamin D 18ug/L (NR 30-100)]. She was started on oral calcium carbonate, calcitriol and cholecalciferol aiming for normocalcemia. Evidence for underlying primary hyperparathyroidism were sought for, which showed osteitis fibrosa cystica, severe osteoporosis and an ossifying fibroma of the mandible, suggesting underlying hyperparathyroidism-jaw tumour-syndrome. The intra-operative histology was reported as oncocytic carcinoma with angio- and perineural invasion, presumed to be thyroid in origin. Given our suspicion of underlying primary hyperparathyroidism, we requested our pathology colleagues to perform additional immunochemical stains, which stained diffusely positive for parathyroid hormone, GATA3 but were negative for thyroglobulin, thyroid transcriptor factor-1, confirming its parathyroid origin. Her hungry bone syndrome resolved 22 weeks post-operatively. Till present (14 months post-operatively), her calcium and PTH levels remain normal and ultrasound of the neck did not reveal any evidence of recurrence. She declined genetic screening. Clinical Lesson: A high index of suspicion is required for the diagnosis of parathyroid carcinoma. In a patient who presents with constitutional symptoms and a neck mass, it is imperative to consider parathyroid disease as a differential diagnosis. A lesion with oncocytic morphology may be of parathyroid or thyroid origin, and the use of immunochemical stains can help differentiate them. Effective communication between clinicians and pathologists is essential in clinching the correct cytopathological diagnosis. Presentation: 6/3/2024

6918 A Unique Case of Oncocytic Thyroid Cancer with an NBN Gene Pathogenic Variant

Abstract Disclosure: A. Grover: None. S. Jhawar: None. S. Shekhar: None. S.A. Avadhanula: None. G. Al-Naqeeb: None. G. Thota: None. P. Veeraraghavan: None. C. Cochran: None. M.Y. Kao-Hsieh: None. A. Gharib: None. F.E. Escorcia: None. J. Del Rivero: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. Introduction: Oncocytic thyroid carcinoma (OTC), previously known as “Hürthle cell” carcinoma, makes up less than 5% of all thyroid cancers. OTCs are often aggressive with a high risk of metastasis, and a poorer prognosis compared to other forms of differentiated thyroid carcinoma (DTC). Molecular drivers of OTC include pathogenic variants (PVs) in NRAS, DAXX, CDKN1A, the mitochondrial genome and chromosomal alterations. PVs in the NBN gene in OTC have not been previously reported. Case: A 53-year-old male was noted to have a thyroid nodule on a routine physical examination. Patient denied any hyper/hypothyroid or compressive symptoms, and family history was unremarkable. Cytopathologic analysis of the fine needle aspiration biopsy of the nodule was consistent with a thyroid follicular neoplasm (Bethesda IV). A total thyroidectomy with central compartment neck dissection was performed. Histopathologic examination demonstrated a 7 cm x 4 cm x 4 cm OTC with capsular and lymphovascular invasion, but without extra-thyroidal extension or lymph node metastasis (pT3aN0Mx). Subsequently, adjuvant radioiodine (RAI) I131 therapy with 165 mCi was administered and post-therapy scan revealed neck uptake. One-year post-therapy RAI diagnostic scan was negative. Three years following the initial thyroid surgery, elevated serum thyroglobulin (Tg) levels were noted. A computed tomogram of the chest revealed multiple bilateral lung nodules. Further imaging ruled out involvement of other distant sites. A diagnostic lower lung wedge resection demonstrated metastatic OTC. The tumor stained positive for CK7, PAX8, TG, TTF-1 and negative for CK20 on immunohistochemistry. Next-generation sequencing of the tumor tissue (Oncomine Comprehensive Assay v3) revealed a PV in the NBN gene (c.2166_2167delGCinsAT; p.Trp722Ter). A year later, the serum Tg levels continued to rise, and the lung nodules had increased in size. Due to disease progression, lenvatinib was initiated. A [F18]-fluorodeoxyglucose positron emission tomography performed one year later demonstrated persistent pulmonary tumor burden with new osseous metastasis in the right scapula, left acetabulum, and the sternum. Zoledronic acid was initiated for the treatment of the skeletal metastases, and palliative external beam radiation (2000 cGy in 5 fractions) was administered to the sternal lesion to alleviate the bone pain. Conclusion: The NBN gene encodes for the protein nibrin, a member of the MRE11/RAD50 complex that is involved in DNA repair. PVs in NBN are commonly identified in non-thyroidal malignancies such as breast and lung carcinomas. While NBN PVs are rarely reported in DTCs, as per our knowledge, this is the first described case of OTC with a PV in NBN as the molecular driver, manifesting with an aggressive disease course. Identification of this novel PV therefore adds to the current knowledge of the molecular landscape of OTC. Presentation: 6/3/2024

12363 A Unique Case Of hüRthle Cell Carcinoma of the Thyroid Gland and Meningioma

Abstract Disclosure: I. Elsayed: None. R. Khan: None. H. Dhaliwal: None. Introduction: MEN1 gene is a tumor suppressor gene on chromosome 11q13 that encodes the nuclear protein menin, which regulates cell growth and cycle. When menin protein is deficient, MEN1 develops. MEN1 mutation usually involves tumors within the parathyroid glands, pancreas, or pituitary. Case Description: A 66-year-old male with past medical history of hypertension, hyperlipidemia, and coronary artery disease presented with sudden onset dizziness, nausea and vomiting for 1 hour. He had similar symptoms on and off for several months, however on the day of presentation, these symptoms were much more acute and severe. Stroke work-up was done including CT and CTA head which revealed a 1.7cm enhancing lesion to R temporal lobe with surrounding edema with an incidental 3 x 3 cm heterogeneous mass in the large portion of the right thyroid gland. Steroids initiated. MRI brain imaging revealed findings consistent with meningioma with local mass effect and pronounced parenchymal edema. Patient underwent successful resection of the mass and pathology confirmed diagnosis of Meningioma, WHO Grade 1. Ear Nose Throat specialist was consulted for incidental thyroid mass. Ultrasound guided Fine needle aspiration biopsy was, Pathology report returned suspicious for follicular neoplasm, Hürthle cell-type. Patient initially underwent right substernal semi-thyroidectomy. Pathology confirmed diagnosis of Oncocytic (Hürthle cell) carcinoma, minimally invasive, 4.3 cm with a single focus of capsular invasion, negative for lymphovascular invasion Discussion: This case presents a 66-year-old male with a rare coexistence of two distinct tumors: a meningioma and a Hürthle cell carcinoma of the thyroid gland. While meningiomas and Hürthle cell carcinoma are not commonly associated with MEN1 syndrome, there have been reports of atypical cases with unusual tumor associations. MEN1 is usually characterized by abnormalities in at least two affected endocrine glands, but variations can involve other endocrine and non-endocrine tumors as well. 25% of thyroid disease can be seen in MEN 1 syndrome; typically papillary thyroid cancer. Only one case in literature found Hürthle cell carcinoma and meningioma in the setting of MEN-1 phenotype. A second case unique case was Hürthle cell carcinoma with metastases to the meninges. The discovery of both a meningioma and a Hürthle cell carcinoma in this patient emphasizes the importance of clinicians being vigilant for the possibility of multiple neoplasms. This case highlights that there may be a relation between role of MEN1 with atypical neoplasms not commonly seen. Presentation: 6/2/2024

Catching the Silent Culprits: TERT Promoter Mutation Screening of Minimally Invasive Follicular and Oncocytic Thyroid Carcinoma in Clinical Practice.

De-escalation of thyroid cancer treatment is crucial to prevent overtreatment of indolent disease, but it remains important to identify clinically aggressive cases. TERT promoter mutations are molecular events frequently associated with high-risk thyroid tumors with poor outcomes and may identify cases at risk of dissemination. In various international guidelines, small minimally invasive follicular thyroid carcinoma and oncocytic thyroid carcinoma (miFTC/miOTC) are classified as low-risk lesions and are not recommended adjuvant treatment. Our study aimed to explore the association between size-based risk assessment and TERT promoter mutations. Between 2019 and May 2024, 84 miFTCs/miOTCs diagnosed at our department underwent digital droplet PCR analysis targeting TERT promoter mutational hotspots C228T and C250T in clinical routine. TERT promoter mutations were found in 10 out of 84 cases (11.9%). Mutated cases were pT1 (n = 1), pT2 (n = 3), or pT3 (n = 6). Patients with mutated tumors were older compared to patients with wild-type tumors (median age of 71years vs. 57years, p = 0.041). There were no significant differences regarding patient sex, tumor size, Ki-67 labeling index, or the presence of distant metastases. Notably, 30% of mutations displayed variant allele frequencies < 10%, possibly suggesting subclonal events. To conclude, TERT promoter mutations in miFTCs and miOTCs were associated with higher patient age and were often suspected to be subclonal. However, they did not affect clinical outcomes, possibly due to short follow-up. Reflex testing for this genetic alteration in miFTCs and miOTCs could be justified regardless of tumor size, though the clinical benefit remains uncertain.

Molecular Markers in Follicular and Oncocytic Thyroid Carcinomas: Clinical Application of Molecular Genetic Testing.

Oncocytic thyroid carcinoma (OTC) was previously considered a variant of follicular thyroid carcinoma (FTC) but has recently been reclassified as a separate form of thyroid cancer. This study aimed to demonstrate that FTC and OTC are fundamentally distinct entities that can potentially be differentiated preoperatively through cytology and/or molecular testing. A retrospective chart review of patients diagnosed with FTC and OTC operated upon at two university health centers from January 2016 to September 2023 (n = 3219) was conducted. Molecular testing results were correlated with histopathologic diagnosis. Fifty patients met the inclusion criteria. FTC was identified in 27 (54.0%) patients, and OTC in 23 (46.0%) patients. Patients with OTC were older (61.8 years) than FTC patients (51.2 years) (p = 0.013). Moreover, aggressive tumors were found in 39.1% (9/23) of OTCs compared to 11.1% (3/27) of FTCs (p = 0.021). Amongst Bethesda category III and IV nodules, 17 out of 20 (85.0%) OTC cytology reports demonstrated an oncocytic subtype compared to only 5 out of 24 FTC cytology reports (20.8%) (p = 0.002). On molecular testing, the EIF1AX alteration was exclusively present in OTCs while the PAX8/PPARy and PTEN alterations were exclusively found in FTCs. Copy number alterations (CNAs) were found to be more prevalent in OTC (66.7%) compared to FTC (33.3%), and they were not indicative of tumor aggressiveness. Within the OTC group, all three patients who had a TP53 alteration were diagnosed with aggressive cancer. Lastly, the OTCs exhibited a higher frequency of multiple alterations on molecular testing (66.7%) compared to FTCs (33.3%). To our knowledge, this is the largest study to date comparing the clinical application of abnormalities found on molecular testing for FTC and OTC. It further demonstrates the distinct clinicopathological and molecular characteristics of OTC.

Minimal Invasive Resection of Large Retrosternal Thyroid Goiter.

Resecting a large goiter extending into the retrosternal space is challenging, especially when a sternotomy or thoracotomy is required. The transthoracic approach is linked to higher postoperative morbidity, reaching up to 30% when compared to the transcervical approach. Although alternative options like thoracoscopic resection have shown promising results, the morbidity of mediastinal dissection remains a concern. Thoracoscopic-assisted transcervical approach might be a feasible, less invasive alternative. This video outlines the steps and potential pitfalls of the procedure. The patient is positioned supine with an extended neck. Initially, the endocrine surgeon mobilizes the thyroid gland through cervical access. If a transcervical resection is not feasible, the patient is mobilized into a lateral decubitus position, and a second team thoracoscopically guides the mediastinal tumor through the thoracic inlet. This allows a stepwise controlled transcervical dissection of the retrosternal mass until complete resection is achieved, thus eliminating the need for mediastinal dissection. To demonstrate the procedure, we present the case of an 84-year-old male with lymph node-positive oncocytic thyroid carcinoma and a large retrosternal goiter extending posteriorly into the mediastinum up to the aortic arch. Thoracoscopic-assisted transcervical resection was performed. The recurrent laryngeal nerve was identified and monitored with a neurostimulation device during dissection. No palsy was noted in the postoperative evaluation. The patient had an uneventful postoperative course and was discharged on the second postoperative day. Thoracoscopic-assisted transcervical resection of large retrosternal goiter seems a feasible alternative to mitigate risks associated with thoracotomy, sternotomy, or thoracoscopic mediastinal dissection. Potential advantages include decreased postoperative morbidity and length of stay. This technique requires thoracoscopic expertise and may be limited depending on the goiter's size and mediastinal positioning.

Oncocytic intraductal carcinoma of parotid gland with a novel AGK::BRAF gene fusion.

Oncocytic intraductal carcinoma of parotid gland with a novel AGK::BRAF gene fusion.

Comparison of prognosis between oncocytic thyroid carcinoma and follicular thyroid carcinoma: a population-based propensity score matching analysis.

Oncocytic thyroid carcinoma (OTC) is a rare subtype of thyroid cancer known for its distinctive morphology and high likelihood of recurrence, setting it apart from follicular thyroid carcinoma (FTC). Despite this, there is limited research comparing the clinicopathological characteristics and outcomes of OTC and FTC. We retrospectively searched through the Surveillance, Epidemiology, and End-Results (SEER) database (2004-2015) for histologically diagnosed OTC and FTC patients. Kaplan-Meier analysis, propensity score matching (PSM), univariate Cox proportional risk regression model, and subgroup analysis were employed to investigate the prognostic effect of clinicopathological features and treatment regimens on survival outcomes of OTC and FTC patients. 2329 OTC patients and 5679 FTC patients were included in the study. OTC patients were prone to older age, white race, lymph node metastasis, distal metastasis, extension and multiple primary tumors compared with FTC patients. After using a 1:1 PSM matching ratio, there were no significant differences in demographic and clinicopathological characteristics between the matched groups. Further Cox regression analysis showed that OTC patients had lower overall survival (OS) and cancer-specific survival (CSS) in contrast with FTC patients. Subgroup survival analysis suggested that the OTC patients were related to lower OS in subgroups including those over 55years old, male sex, white ethnicity, extrathyroidal extension, single primary tumor, surgery and without chemotherapy compared with the FTC patients in these subgroups. In addition, the OTC patients were connected with lower CSS in subgroups including male sex, white ethnicity, married status, tumor size is less than 20mm or more than 40mm, N0 stage, localized stage, single primary tumor, surgery, radiotherapy, and without chemotherapy compared with the FTC patients in these subgroups. Meanwhile, the OTC patients had lower CSS compared to FTC patients regardless of age and extrathyroidal extension. The results suggested that OTC patients have unique clinical features and poorer prognoses compared to FTC patients. Surgical resection and radioactive iodine therapy are recommended for OTC patients and FTC patients. It is worth noting that the prognosis of OTC relies largely on the selection of treatment strategies. Therefore, our results highlighted the clinical significance of the early distinguishment and the correct choice of treatment in OTC patients.

EIF1AX mutation in thyroid nodules: a histopathologic analysis of 56 cases in the context of institutional practices.

EIF1AX mutation has been identified as a driver mutation for papillary thyroid carcinoma (PTC) by The Cancer Genome Atlas (TCGA) study. Subsequent studies confirmed this mutation in PTC and Anaplastic Thyroid Carcinoma (ATC) but also reported EIF1AX mutation in Follicular nodular disease (FND) and benign thyroid nodules. In this study, we review thyroid nodules with EIF1AX mutation from two institutions: a tertiary care hospital (YNHH, n = 22) and a major cancer referral center (MSKCC, n = 34) and report the varying histomorphology in the context of additional genetic abnormalities and institutional practices. Pathology diagnoses were reviewed according to the WHO 5th edition and correlated with the type of EIF1AX mutation and additional concurrent molecular alterations, if any. Most cases were splice site type mutations. Cases consisted of 9 FND, 7 follicular (FA) or oncocytic adenomas (OA), 2 non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) and 38 follicular-cell derived thyroid carcinomas. Of 8 cases with isolated EIF1AX mutation, 7 were FND, FA or OA (88%) and one was an oncocytic carcinoma (12%). Of 12 cases with EIF1AX and one additional molecular alteration, 9 (75%) were FND, FA or OA, 2 (17%) were NIFTPs and one (8%) was a poorly differentiated thyroid carcinoma. All 36 cases with EIF1AX mutation and molecular alterations were malignant (100%) and included TP53 and TERT promoter mutations associated with ATC (n = 8) and high-grade follicular cell-derived non-anaplastic carcinoma (HGC, n = 2). Isolated EIF1AX mutation was noted only in thyroid nodules seen at YNHH and were predominantly encountered in benign thyroid nodules including FND. Accumulation of additional genetic abnormalities appears to be progressively associated with malignant tumors.

Predictive Factors of Radioactive Iodine Therapy Refractoriness in Patients with Differentiated Thyroid Carcinoma.

Aim Differentiated thyroid carcinoma (DTC) is the most prevalent endocrine malignancy, with radioactive iodine (RAI) therapy being a standard of care. However, RAI refractoriness, occurring in a subset of patients, significantly impacts survival rates. Understanding predictive factors for RAI refractoriness is crucial for optimizing patient management. Methods This retrospective study analyzed data from 90 DTC patients at Ibn Sina University Hospital, Morocco. Patients were categorized into RAI-refractory (RAIR) and non-RAIR groups based on established criteria. Statistical analyses, including univariate and multivariate logistic regression, were performed to identify predictive factors of RAI refractoriness. Results Age at the time of diagnosis ≥ 54 years, primary tumor diameter ≥ 29 mm, and distal/nodal metastasis were independent predictors of RAIR-DTC. Additionally, the oncocytic carcinoma histological subtype significantly increased the risk of refractoriness. These findings were consistent with previous studies and underscored the importance of early detection and risk stratification. Conclusion Recognition of predictive factors for RAI refractoriness, including age, tumor size, distal/nodal metastasis, and histological subtype, facilitates early identification of high-risk patients. This enables timely intervention and personalized treatment strategies, particularly relevant in resource-limited settings. Further prospective studies are warranted to validate these findings and explore additional molecular markers for improved prediction of RAI refractoriness.

Impact of reclassification of oncocytic and follicular thyroid carcinoma by the 2022 who classification

Impact of reclassification of oncocytic and follicular thyroid carcinoma by the 2022 who classification

Impact of Reclassification of Oncocytic and Follicular Thyroid Carcinoma by the 2022 WHO Classification.

The 2022 WHO Classification categorizes oncocytic (OTC) and follicular thyroid carcinoma (FTC) based on the degree of capsular and vascular invasion into minimally invasive (MI), encapsulated angioinvasive (EA) and widely invasive tumors (WI). While associations with clinical outcomes have been studied extensively in FTC, robust clinical data are lacking for OTC. We aimed to investigate the impact of the reclassification of OTC and FTC by the 2022 WHO Classification on clinical outcomes. All adult OTC and FTC patients treated at the Erasmus MC (the Netherlands) between 2000 and 2016 were retrospectively included. All tumors were extensively revised by two independent pathologists, facilitated by Palga: Dutch Pathology Databank. Kaplan-Meier curves were used to study the association of the 2004 and 2022 WHO Classification with overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and radioactive iodine (RAI) refractory disease. Fifty-two OTC and 89 FTC patients were included, of which 15 (28.8%) OTC and 34 (38.2%) FTC tumors were reclassified as EAOTC or EAFTC. The 2022 WHO Classification substantially improved risk stratification in both subtypes for DSS, compared with the 2004 edition. Ten-year DSS rates were 100% for MIOTC, 92.9% for EAOTC and 56.5% for WIOTC, compared to 100% (MIOTC) and 64.2% (WIOTC) following the 2004 WHO Classification. For FTC and RAI-refractory disease, similar trends were observed. Classification of OTC and FTC into three subcategories as defined by the 2022 WHO Classification substantially improves discrimination between low, intermediate and high risk patients, especially for DSS and RAI-refractory disease.