Encapsulated Papillary Oncocytic Neoplasms of the Thyroid: Morphologic, Immunohistochemical, and Molecular Analysis of 18 Cases
Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA.The American journal of surgical pathology (Impact Factor: 5.15). 09/2010; 34(11):1582-90. DOI: 10.1097/PAS.0b013e3181f2d820
Encapsulated papillary oncocytic neoplasms (EPONs) of the thyroid are rare tumors, whose relationship to other thyroid tumors has not been thoroughly elucidated. Earlier, they have been regarded as variants of papillary thyroid carcinoma (PTC), hyperplastic lesions, and follicular neoplasms. Eighteen EPONs were retrieved from our surgical pathology files and reviewed for defining morphologic features. Cases having the typical nuclear features of PTC were excluded. Immunohistochemistry (IHC) for CK19, HBME1, and CD56 was carried out. Microdissection, polymerase chain reaction, and sequencing of exon 15 of the BRAF gene were completed. Cases were evaluated for rearranged in transformation/papillary thyroid carcinoma RET/PTC rearrangement by fluorescent in situ hybridization (FISH). The majority of the tumors exhibited a distinctive histologic appearance. They were composed of true papillae lined by a single layer of predominantly cuboidal cells with oncocytic cytoplasm; hobnailing was typically prominent. Three tumors showed taller cells with uniformly apical nuclei and no hobnailing. Ten of 18 cases showed vascular and/or capsular invasion; hence, if the diagnostic criteria used to evaluate follicular neoplasms are applied, more than half of the tumors would be considered minimally invasive carcinomas. No cases were immunoreactive with antibodies to HBME1, whereas only 1 of 13 was immunoreactive for CK19. Six of 7 interpretable cases were immunoreactive for CD56. No BRAF point mutations or RET/PTC rearrangements were identified in the examined cases. All patients were alive at the time of last follow-up and no locally recurrent disease had been reported; however, 1 case was remarkable for a lymph node metastasis. Our results confirm that EPONs are histologically, immunohistochemically, and molecularly distinct from papillary thyroid carcinoma and seem to be most related to follicular neoplasms.
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- "With this analysis we identified the regions that were differentially gained, lost or amplified between the 14 oncocytic and 11 non-oncocytic thyroid samples. A more complex genomic constellation is appreciated in the oncocytic group, strengthening the hypothesis that CNAs might Table 2. Summary of canonical BRAF and RAS hot-spot mutations frequency in oncocytic thyroid le- sions Reference Type of Analyzed oncocytic samples (n= case number) BRAF V600E mutation frequency (type of mutated thyroid tumor) H-, N-, K-RAS mutations frequency (type of mutated thyroid tumor)  FTC-O (n=11) NP 55% (FTC-O)  FA-O, FTC-O (n=11) NP 9.1% (FTC-O)  FTC-O (n=3) 0% NP  FTC-O, FA-O (n=22) 0% NP  FTC-O, FA-O (n=32) NP 9.4% (FTC-O, FA-O)  FA-O, FTC-O, PTC-O (n=39)^ 27.3% (PTC-O) NP  FTC-O (n=9) 0% 0% §  PTC-O -FV (n=3) 0% 0%  FA-O, FTC-O, PTC-O (n= 44) 0% 0%  FA-O, FTC-O (n=70) NP 11.4% (FTC-O)  PTC-O (n=9) 0% NP  FTC-O, PTC-O (n=13) 23% (PTC-O) 0%  PTC-O (n=8) 87.5% (PTC-O) NP  FTC-O, FA-O (n=20) 0% 5.8% (FTC-O)  FA-O, FTC-O, (n=27) 0% 11% (FTC-O) Present study Hyp-O, FA-O, PTC-O, FTC-O (n=14) 0% 0% ^Warthin-like PTCs were not considered; §Only N-RAS gene was analyzed. aCGH profiling of oncocytic thyroid lesions 1962 Am J Cancer Res 2015;5(6):1954-1971 contribute to development of oncocytic phenotype (Figure 5). "
ABSTRACT: Oncocytic change is the result of aberrant mitochondrial hyperplasia, which may occur in both neoplastic and non-neoplastic cells and is not infrequent in the thyroid. Despite being a well-characterized histologic phenotype, the molecular causes underlying such a distinctive cellular change are poorly understood. To identify potential genetic causes for the oncocytic phenotype in thyroid, we analyzed copy number alterations in a set of oncocytic (n=21) and non-oncocytic (n=20) thyroid lesions by high-resolution microarray-based comparative genomic hybridization (aCGH). Each group comprised lesions of diverse histologic types, including hyperplastic nodules, adenomas and carcinomas. Unsupervised hierarchical clustering of categorical aCGH data resulted in two distinct branches, one of which was significantly enriched for samples with the oncocytic phenotype, regardless of histologic type. Analysis of aCGH events showed that the oncocytic group harbored a significantly higher number of genes involved in copy number gains, when compared to that of conventional thyroid lesions. Functional annotation demonstrated an enrichment for copy number gains that affect genes encoding activators of mitochondrial biogenesis in oncocytic cases but not in their non-oncocytic counterparts. Taken together, our data suggest that genomic alterations may represent additional/alternative mechanisms underlying the development of the oncocytic phenotype in the thyroid.
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- "From a clinical standpoint, the negative aspect of Hürthle cell FTC and Hürthle cell PTC is their lesser ability to trap iodine, thus rendering them less responsive to radioactive iodine (Rosai et al. 1992, LiVolsi et al. 2004, Sobrinho-Simões et al. 2011). A last point to refer that despite the 'old' idea that Hürthle cell FTCs tended to carry a guarded prognosis, there is consistent evidence showing that encapsulated, nonangioinvasive Hürthle cell FTC and Hürthle cell PTC carry, like their non-Hürthle cell counterparts, an excellent prognosis even after being treated conservatively (Widder et al. 2008, Piana et al. 2010, Woodford et al. 2010, Sobrinho-Simões et al. 2011). Genetics, Hü rthle cell transformation and tumorigenesis The genetics of Hürthle cell FTC has to be divided for the sake of simplicity into two categories: genetic alterations that are linked with the three main histotypes of follicular cell-derived thyroid carcinomas (FTC, PTC, and PDTC) and the genetic alterations that are linked to the acquisition of Hürthle cell features. "
ABSTRACT: The biology and the genetics of Hürthle cell tumors are reviewed starting from the characterization and differential diagnosis of the numerous benign and malignant, neoplastic and nonneoplastic lesions of the thyroid in which Hürthle cell transformation is frequently observed. The clinicopathologic and molecular evidence obtained from the comparative study of the aforementioned conditions indicate that Hürthle cell appearance represents a phenotype that is superimposed on the genotypic and conventional histopathologic features of the tumors. Hürthle cell tumors differ from their non-Hürthle counterparts regarding the prevalence of large deletions of mitochondrial DNA (mtDNA), mutations of mtDNA genes coding for oxidative phosphorylation (OXPHOS) proteins (namely mutations of complex I subunit genes) and mutations of nuclear genes coding also for mitochondrial OXPHOS proteins. Such mitochondrial alterations lead to energy production defects in Hürthle cell tumors; the increased proliferation of mitochondria may reflect a compensatory mechanism for such defects and is associated with the overexpression of factors involved in mitochondrial biogenesis. The mitochondrial abnormalities are also thought to play a major role in the predisposition for necrosis instead of apoptosis which seems to be blocked in most Hürthle cell tumors. Finally, the results obtained in experimental models using cybrid cell lines and the data obtained from histopathologic and molecular studies of familial Hürthle cell tumors are used, together with the aforementioned genetic and epigenetic alterations, to progress in the understanding of the mechanisms through which mitochondrial abnormalities may be involved in the different steps of thyroid carcinogenesis, from tumor initiation to metastization.
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ABSTRACT: de Vries M M, Celestino R, Castro P, Eloy C, Máximo V, van der Wal J E, Plukker J T M, Links T P, Hofstra R M W, Sobrinho-Simões M & Soares P (2012) Histopathology 61, 833–843 RET/PTC rearrangement is prevalent in follicular Hürthle cell carcinomas Aims: The molecular alterations underlying follicular Hürthle cell carcinomas (FHCCs) are largely unknown. In an attempt to clarify this issue, we analysed a series of Hürthle cell tumours for the presence of RET/PTC and PAX8/PPARG rearrangements and BRAF, HRAS and NRAS mutations. Methods and results: We investigated a series of 20 follicular Hürthle cell tumours [17 FHCCs and three follicular Hürthle cell adenomas (FHCAs)]. RET/PTC rearrangements were found in 33% of FHCAs and in 38% of FHCCs. All RET/PTC-positive FHCCs had a solid pattern of growth. PAX8/PPARG rearrangement was present in 27% of the FHCCs which displayed, in most cases, a follicular architecture. NRAS mutation was detected in one FHCC. An FHCC with a solid/microfollicular growth pattern scored positive for both RET/PTC and PAX8/PPARG rearrangement. Conclusions: Our study has shown a significant association between RET/PTC rearrangements and FHCCs with a solid growth pattern, thus raising the possibility of using tyrosine kinase inhibitors for the treatment of patients with FHCCs, which are often refractory to radioiodine treatment.
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