Materiały źródłowe

• #1 Oncocytic (Hürthle Cell) Thyroid Carcinoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK568736/

  Oncocytic carcinoma, previously known as Hrthle cell carcinoma, is a rare type of thyroid cancer originating from oncocytic cells, a specialized type of follicular thyroid cell. These cells are identified by their eosinophilic cytoplasm and an abundance of granular cytoplasm. Until 2022, oncocytic carcinoma was considered a variant of follicular thyroid carcinoma, but it has since been reclassified as a separate subtype by the World Health Organization (WHO). Oncocytic thyroid carcinoma’s distinct histopathological features and molecular differences, particularly mutations in the mitochondrial genome and gene expression profiles, set it apart from follicular thyroid carcinoma.[1] […] Various genetic, environmental, and biological factors influence the development of oncocytic thyroid cancer. This type of cancer originates from specialized follicular thyroid cells called oncocytes, characterized by their abundant eosinophilic cytoplasm and high mitochondrial content. The pathogenesis of oncocytic cancer is associated with specific genetic mutations, particularly in mitochondrial DNA, and changes in nuclear genes. Mutations in oncogenes like BRAF and HRAS and inactivation of tumor suppressor genes (eg, PTEN) have been identified, indicating a disruption of normal cellular signaling pathways that control cell growth and survival.[2]

• #2 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7793513/

  Hrthle cell carcinoma (HCC) represents 34% of thyroid carcinoma cases. […] It is considered to be more aggressive than non-oncocytic thyroid carcinomas. […] However, due to its rarity, the pathological characteristics and biological behavior of HCC remain to be elucidated. […] The Hrthle cell is characterized cytologically as a large cell with abundant eosinophilic, granular cytoplasm, and a large hyperchromatic nucleus with a prominent nucleolus. […] Cytoplasmic granularity is due to the presence of numerous mitochondria. […] Molecular changes involve cellular signaling pathways and mitochondria-related DNA. […] The cellular origin of HCC, as well as other thyroid cancer types, is still not completely understood. […] The high prevalence of Hrthle cell changing into thyroid lesions may reflect high oxidative stress and reactive oxygen species production in thyroid cells during normal iodine and thyroid hormone metabolism.

• #3 Hurthle Cell Carcinoma (Oncocytic Carcinoma): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/279462-overview

  Hrthle cell cancer reportedly behaves in a more aggressive fashion than other well-differentiated thyroid cancers, with a tendency to higher frequency of metastasis and a lower survival rate. […] The RAS oncogene is frequently involved in the pathogenesis of Hrthle cell tumors. […] An association also was found between overexpression of the p53 gene product and a subset of Hrthle cell carcinomas. […] Evidence suggests that some Hrthle cell adenomas and carcinomas can express an RET/PTC gene arrangement. […] Mitochondrion-related alterations, such as mutations in mitochondrial DNA, are also described in Hrthle cell tumors. […] Activating gene mutations encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein are also reported in some follicular carcinomas. […] A study analyzing genomic dissection of Hurthle cell carcinoma indicated that Hurthle cell carcinoma could be a unique type of malignancy.

• #4 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7793513/

  Hrthle cell carcinoma (HCC) represents 34% of thyroid carcinoma cases. […] It is considered to be more aggressive than non-oncocytic thyroid carcinomas. […] However, due to its rarity, the pathological characteristics and biological behavior of HCC remain to be elucidated. […] The Hrthle cell is characterized cytologically as a large cell with abundant eosinophilic, granular cytoplasm, and a large hyperchromatic nucleus with a prominent nucleolus. […] Cytoplasmic granularity is due to the presence of numerous mitochondria. […] Molecular changes involve cellular signaling pathways and mitochondria-related DNA. […] The cellular origin of HCC, as well as other thyroid cancer types, is still not completely understood. […] The high prevalence of Hrthle cell changing into thyroid lesions may reflect high oxidative stress and reactive oxygen species production in thyroid cells during normal iodine and thyroid hormone metabolism.

• #5 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7793513/

  Hrthle cell carcinoma (HCC) represents 34% of thyroid carcinoma cases. […] It is considered to be more aggressive than non-oncocytic thyroid carcinomas. […] However, due to its rarity, the pathological characteristics and biological behavior of HCC remain to be elucidated. […] The Hrthle cell is characterized cytologically as a large cell with abundant eosinophilic, granular cytoplasm, and a large hyperchromatic nucleus with a prominent nucleolus. […] Cytoplasmic granularity is due to the presence of numerous mitochondria. […] Molecular changes involve cellular signaling pathways and mitochondria-related DNA. […] The cellular origin of HCC, as well as other thyroid cancer types, is still not completely understood. […] The high prevalence of Hrthle cell changing into thyroid lesions may reflect high oxidative stress and reactive oxygen species production in thyroid cells during normal iodine and thyroid hormone metabolism.

• #6 Oncocytic (Hürthle Cell) Thyroid Carcinoma | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/131177

  Various genetic, environmental, and biological factors influence the development of oncocytic thyroid cancer. This type of cancer originates from specialized follicular thyroid cells called oncocytes, characterized by their abundant eosinophilic cytoplasm and high mitochondrial content. The pathogenesis of oncocytic cancer is associated with specific genetic mutations, particularly in mitochondrial DNA, and changes in nuclear genes. Mutations in oncogenes like BRAF and HRAS and inactivation of tumor suppressor genes (eg, PTEN) have been identified, indicating a disruption of normal cellular signaling pathways that control cell growth and survival.[2] […] The cancer is linked to changes in the mitochondria, driven by mutations in mitochondrial DNA (mtDNA), including small mutations and larger deletions, leading to compromised energy production and subsequent compensatory mitochondrial proliferation within the cell.[6]

• #7 Oncocytic (Hürthle Cell) Thyroid Carcinoma | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/131177

  Histopathologically, oncocytic carcinoma is distinguished by a high density of oncocytic cells, often accompanied by vascular invasion and a tendency for extra-thyroidal extension. Thyroid tumors are classified as oncocytic neoplasms when more than 75% of the tumor comprises oncocytic cells.[8] This aggressive behavior stems partly from the tumor’s capacity to invade surrounding tissues and metastasize to distant sites such as the lungs and bones.[9]

• #8 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://www.mdpi.com/2072-6694/13/1/26

  Hürthle cell carcinoma (HCC) represents 3–4% of thyroid carcinoma cases. […] HCC has been considered as a more aggressive form of carcinoma compared to non-oncocytic thyroid carcinomas. […] The cellular origin of HCC, as well as other thyroid cancer types, is still not completely understood. Thyroid cancer stem cell (CSC) model is one hypothesis to explain thyroid carcinogenesis. […] The genetic profile of HCC differs from papillary thyroid carcinoma and follicular thyroid carcinoma. […] HCC shows changes in both nuclear DNA and mitochondrial DNA (mtDNA). Molecular changes in nuclear DNA involve several signaling pathways and mitochondrial functions. […] The high prevalence of Hürthle cell changing into thyroid lesions may reflect high oxidative stress and reactive oxygen species production in thyroid cells during normal iodine and thyroid hormone metabolism. […] Mitochondrial mutations may play a part as one of many factors leading to tumor development.

• #9 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7793513/

  Molecular pathways that differentiate Hrthle cell adenoma from HCC with wide invasiveness included the PIK3CA-Akt-mTOR and Wnt, providing rationale toward new targets of this type of malignancy. […] A significant difference in oncogene expression between follicular thyroid carcinoma (FTC) and HCC suggests that despite having a common origin in the follicular cell, follicular thyroid carcinoma and HCC should be considered as two separate entities. […] HCC shows changes in both nuclear DNA and mitochondrial DNA (mtDNA). […] Mitochondrial genetic changes involve interaction between mutations in the mitochondrial and nuclear genomes. […] The mitochondrial DNA (mtDNA) is small, and incorporates a sequence of 16,569 bp, encoding 13 essential components in cellular energy production. […] Mitochondrial DNA (mtDNA) is more susceptible than nuclear DNA to mutagen-induced damage. […] Disruptive mutations in mitochondrial DNA are found in complex I subunit genes in Hrthle cell tumors. […] Mitochondrial mutations may play a part as one of many factors leading to tumor development.

• #10 Hurthle Cell Carcinoma (Oncocytic Carcinoma): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/279462-overview

  Hrthle cell cancer reportedly behaves in a more aggressive fashion than other well-differentiated thyroid cancers, with a tendency to higher frequency of metastasis and a lower survival rate. […] The RAS oncogene is frequently involved in the pathogenesis of Hrthle cell tumors. […] An association also was found between overexpression of the p53 gene product and a subset of Hrthle cell carcinomas. […] Evidence suggests that some Hrthle cell adenomas and carcinomas can express an RET/PTC gene arrangement. […] Mitochondrion-related alterations, such as mutations in mitochondrial DNA, are also described in Hrthle cell tumors. […] Activating gene mutations encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein are also reported in some follicular carcinomas. […] A study analyzing genomic dissection of Hurthle cell carcinoma indicated that Hurthle cell carcinoma could be a unique type of malignancy.

• #11 Hurthle Cell Tumors of the Thyroid | Ento Key

  https://entokey.com/hurthle-cell-tumors-of-the-thyroid/

  As yet, there is no clear association between HCCs and environmental or infective carcinogens. […] It is widely believed that progressive transformation of normal cells toward increasingly more malignant cell types through a stepwise accumulation of somatic mutations of genes underlies the pathogenesis of Hurthle cell tumors. […] Oncogenic activation by gene mutations and chromosomal translocations has been shown to be common in thyroid cancers. […] The Ras oncogene has been shown to be one of the most prevalent oncogenes to be activated in well-differentiated follicular thyroid cancers including Hurthle cell carcinomas. […] Taken together, these studies suggest a papillary lineage in many HCCs and the potentially critical role of ret/PTC mutation (and other genetic abnormalities) in the development of this subset Hurthle cell tumors.

• #12 Hurthle Cell Carcinoma (Oncocytic Carcinoma): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/279462-overview

  Hrthle cell cancer reportedly behaves in a more aggressive fashion than other well-differentiated thyroid cancers, with a tendency to higher frequency of metastasis and a lower survival rate. […] The RAS oncogene is frequently involved in the pathogenesis of Hrthle cell tumors. […] An association also was found between overexpression of the p53 gene product and a subset of Hrthle cell carcinomas. […] Evidence suggests that some Hrthle cell adenomas and carcinomas can express an RET/PTC gene arrangement. […] Mitochondrion-related alterations, such as mutations in mitochondrial DNA, are also described in Hrthle cell tumors. […] Activating gene mutations encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein are also reported in some follicular carcinomas. […] A study analyzing genomic dissection of Hurthle cell carcinoma indicated that Hurthle cell carcinoma could be a unique type of malignancy.

• #13 Hurthle Cell Carcinoma (Oncocytic Carcinoma): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/279462-overview

  Hrthle cell cancer reportedly behaves in a more aggressive fashion than other well-differentiated thyroid cancers, with a tendency to higher frequency of metastasis and a lower survival rate. […] The RAS oncogene is frequently involved in the pathogenesis of Hrthle cell tumors. […] An association also was found between overexpression of the p53 gene product and a subset of Hrthle cell carcinomas. […] Evidence suggests that some Hrthle cell adenomas and carcinomas can express an RET/PTC gene arrangement. […] Mitochondrion-related alterations, such as mutations in mitochondrial DNA, are also described in Hrthle cell tumors. […] Activating gene mutations encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein are also reported in some follicular carcinomas. […] A study analyzing genomic dissection of Hurthle cell carcinoma indicated that Hurthle cell carcinoma could be a unique type of malignancy.

• #14 Concurrence of Papillary Thyroid Carcinoma and Hürthle Cell Carcinoma in an Iranian Woman with Hashimoto’s Thyroiditis

  https://ijp.iranpath.org/article_36557.html

  The most usual form of the endocrine carcinoma is thyroid cancer (TC). […] Recent studies revealed incidence of RET/PTC rearrangement in other tumors, like Hrthle cell carcinoma (HCC) and even in non-carcinomatous disorders like Hashimoto’s thyroiditis. […] Concurrence of papillary carcinoma and Hrthle cell carcinoma is a rare form of thyroid malignancies, with doubtful cytogenetic findings and biological behaviors. […] The continuous and persistent inflammatory reaction causes cell injury via reactive oxygen species generation (ROS). DNA damaging by ROS causes various mutations that some of them lead to the creation of thyroid malignancy. […] A recent research has shown RET/PTC rearrangement in other tumors like HCC and even in non-carcinomatous disorders like Hashimoto’s thyroiditis.

• #15 Hurthle Cell Carcinoma (Oncocytic Carcinoma): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/279462-overview

  Hrthle cell cancer reportedly behaves in a more aggressive fashion than other well-differentiated thyroid cancers, with a tendency to higher frequency of metastasis and a lower survival rate. […] The RAS oncogene is frequently involved in the pathogenesis of Hrthle cell tumors. […] An association also was found between overexpression of the p53 gene product and a subset of Hrthle cell carcinomas. […] Evidence suggests that some Hrthle cell adenomas and carcinomas can express an RET/PTC gene arrangement. […] Mitochondrion-related alterations, such as mutations in mitochondrial DNA, are also described in Hrthle cell tumors. […] Activating gene mutations encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein are also reported in some follicular carcinomas. […] A study analyzing genomic dissection of Hurthle cell carcinoma indicated that Hurthle cell carcinoma could be a unique type of malignancy.

• #16 The Molecular Landscape of Hürthle Cell Thyroid Cancer Is Associated with Altered Mitochondrial Function—A Comprehensive Review

  https://www.mdpi.com/2073-4409/9/7/1570

  The most common genetic alterations observed in HTC include pathogenic variants in the genes associated with abnormal protein translation, such as EIF1AX, MADCAM1, or DAXX. […] These data suggest that the dysregulation of translation is highly significant for HTC’s pathogenesis. […] Another landmark of HTC, clearly distinguishing it from other types of thyroid cancer, is the widespread loss of heterozygosity (LOH). […] Recent studies also revealed whole-chromosomal duplication appearing in a non-random pattern, particularly in chromosomes 5 and 7, in HTC. […] The aberrant mitochondrial function observed in HTC could promote the shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis as the predominant source of ATP production. […] It is widely accepted that aberrant mitochondrial respiration and dysregulated mitochondrial function can result in increased oxidative stress, which can further lead to oncogenesis.

• #17 Pathology Outlines – Oncocytic (Hürthle cell) tumors

  https://www.pathologyoutlines.com/topic/thyroidhurthle.html

  Follicular neoplasm with more than 75% oncocytic tumor cells […] Oncocytic appearance is due to accumulation of dysfunctional mitochondria […] Malignant if capsular and / or vascular invasion […] Hematogenous metastases, 30% to lymph node (in contrast, rare in follicular carcinoma) […] No known exogenous risk factors for developing oncocytic tumors […] Aneuploidy is common in oncocytic tumors, including chromosome gains and losses […] Deletions or mutation of mitochondrial DNA (mtDNA) coding for oxidative phosphorylation (OXPHOS) proteins, which leads to energy production defects and compensatory mitochondrial proliferation […] PTEN and TP53 mutations […] MEN1 loss of function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma.

• #18 Pathology Outlines – Oncocytic (Hürthle cell) tumors

  https://www.pathologyoutlines.com/topic/thyroidhurthle.html

  Follicular neoplasm with more than 75% oncocytic tumor cells […] Oncocytic appearance is due to accumulation of dysfunctional mitochondria […] Malignant if capsular and / or vascular invasion […] Hematogenous metastases, 30% to lymph node (in contrast, rare in follicular carcinoma) […] No known exogenous risk factors for developing oncocytic tumors […] Aneuploidy is common in oncocytic tumors, including chromosome gains and losses […] Deletions or mutation of mitochondrial DNA (mtDNA) coding for oxidative phosphorylation (OXPHOS) proteins, which leads to energy production defects and compensatory mitochondrial proliferation […] PTEN and TP53 mutations […] MEN1 loss of function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma.

• #19 Oncocytic (Hürthle Cell) Thyroid Carcinoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK568736/

  The cancer is linked to changes in the mitochondria, driven by mutations in mitochondrial DNA (mtDNA), including small mutations and larger deletions, leading to compromised energy production and subsequent compensatory mitochondrial proliferation within the cell.[6] Furthermore, oncocytic tumors exhibit specific alterations in nuclear DNA, although these are less prevalent compared to other thyroid tumors. For instance, mutations in oncogenes like HRAS and BRAF, commonly observed in other types of thyroid cancer, are rare in oncocytic tumors.[7] […] This aggressive behavior stems partly from the tumor’s capacity to invade surrounding tissues and metastasize to distant sites such as the lungs and bones.[9] The vascularization of the tumor microenvironment is also crucial, as increased angiogenesis supports the tumor’s growth and survival.

• #20 The biology and the genetics of Hürthle cell tumors of the thyroid in: Endocrine-Related Cancer Volume 19 Issue 4 (2012)

  https://erc.bioscientifica.com/view/journals/erc/19/4/R131.xml

  The biology and the genetics of Hrthle 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 Hrthle cell transformation is frequently observed. […] Hrthle cell tumors differ from their non-Hrthle 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 Hrthle 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.

• #21 Hürthle cell thyroid carcinoma | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/hurthle-cell-thyroid-carcinoma-3?embed_domain=hackmd.io%2525252F%25252540yIPUAFeCSL2JsU8smR5nJQ%2525252Fbnjhjgjghjghjghfavicon.icofavicon.icoradiopaedia-icon-144.png&lang=us

  Hrthle cell tumors originate from follicular cells within thyroid follicles and they may manifest as benign Hrthle cell adenomas or malignant Hrthle cell carcinomas, with characteristics such as capsular/vascular invasion, infiltration of the thyroid gland, locoregional lymph node involvement, or metastatic spread. […] Germline polymorphisms of the ATPase 6 gene are implicated in the pathogenesis, with an increased prevalence of mitochondrial DNA common deletions in Hrthle cell tumors 2,4.

• #22 Pathology Outlines – Oncocytic (Hürthle cell) tumors

  https://www.pathologyoutlines.com/topic/thyroidhurthle.html

  Follicular neoplasm with more than 75% oncocytic tumor cells […] Oncocytic appearance is due to accumulation of dysfunctional mitochondria […] Malignant if capsular and / or vascular invasion […] Hematogenous metastases, 30% to lymph node (in contrast, rare in follicular carcinoma) […] No known exogenous risk factors for developing oncocytic tumors […] Aneuploidy is common in oncocytic tumors, including chromosome gains and losses […] Deletions or mutation of mitochondrial DNA (mtDNA) coding for oxidative phosphorylation (OXPHOS) proteins, which leads to energy production defects and compensatory mitochondrial proliferation […] PTEN and TP53 mutations […] MEN1 loss of function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma.

• #23 Genetic Drivers in Hürthle Cell Carcinoma – Mass General Advances in Motion

  https://advances.massgeneral.org/oncology/article.aspx?id=1267

  A Massachusetts General Hospital Cancer Center team has identified important genetic drivers in Hrthle cell carcinoma (HCC): widespread chromosomal losses in the cells and mutations in nuclear and mitochondrial DNA. […] The first factor widespread chromosomal loss, leading to loss of heterozygosity (LOH) was especially surprising, and has been observed in the majority of HCC tumors. […] HCC cells are also unusual in that they have many more mitochondria than is normal in cancer cells. In addition to nuclear DNA mutations acting as drivers of the disease, mitochondrial DNA mutations in complex I also appear to drive HCC. […] Widespread chromosomal losses are an early event, says Dr. Gopal, and are maintained even throughout metastasis. This leads to a near-haploid state in which only one copy of most chromosomes is present in the majority of tumors they analyzed.

• #24 Genetic Drivers in Hürthle Cell Carcinoma – Mass General Advances in Motion

  https://advances.massgeneral.org/oncology/article.aspx?id=1267

  The group also identified unique mutational drivers in the nuclear DNA of HCC tumors. […] Combined with the lost copies of genes through LOH, these nuclear mutations could completely inactivate genes whose normal function is to suppress cancer. […] HCC cells are also characterized by an abundance of mitochondria, which are in turn affected by characteristic mutations of their own. […] Based on the data they collected, the authors believe that complex I mitochondrial DNA mutations may be driving the growth of HCC cancer cells. […] The mechanisms by which these mitochondrial DNA mutations actually confer an advantage on cells bearing them, however, remains to be determined.

• #25 Pathology Outlines – Oncocytic (Hürthle cell) tumors

  https://www.pathologyoutlines.com/topic/thyroidhurthle.html

  Follicular neoplasm with more than 75% oncocytic tumor cells […] Oncocytic appearance is due to accumulation of dysfunctional mitochondria […] Malignant if capsular and / or vascular invasion […] Hematogenous metastases, 30% to lymph node (in contrast, rare in follicular carcinoma) […] No known exogenous risk factors for developing oncocytic tumors […] Aneuploidy is common in oncocytic tumors, including chromosome gains and losses […] Deletions or mutation of mitochondrial DNA (mtDNA) coding for oxidative phosphorylation (OXPHOS) proteins, which leads to energy production defects and compensatory mitochondrial proliferation […] PTEN and TP53 mutations […] MEN1 loss of function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma.

• #26 The Molecular Landscape of Hürthle Cell Thyroid Cancer Is Associated with Altered Mitochondrial Function—A Comprehensive Review

  https://www.mdpi.com/2073-4409/9/7/1570

  The most common genetic alterations observed in HTC include pathogenic variants in the genes associated with abnormal protein translation, such as EIF1AX, MADCAM1, or DAXX. […] These data suggest that the dysregulation of translation is highly significant for HTC’s pathogenesis. […] Another landmark of HTC, clearly distinguishing it from other types of thyroid cancer, is the widespread loss of heterozygosity (LOH). […] Recent studies also revealed whole-chromosomal duplication appearing in a non-random pattern, particularly in chromosomes 5 and 7, in HTC. […] The aberrant mitochondrial function observed in HTC could promote the shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis as the predominant source of ATP production. […] It is widely accepted that aberrant mitochondrial respiration and dysregulated mitochondrial function can result in increased oxidative stress, which can further lead to oncogenesis.

• #27 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7793513/

  Hrthle cell carcinoma (HCC) represents 34% of thyroid carcinoma cases. […] It is considered to be more aggressive than non-oncocytic thyroid carcinomas. […] However, due to its rarity, the pathological characteristics and biological behavior of HCC remain to be elucidated. […] The Hrthle cell is characterized cytologically as a large cell with abundant eosinophilic, granular cytoplasm, and a large hyperchromatic nucleus with a prominent nucleolus. […] Cytoplasmic granularity is due to the presence of numerous mitochondria. […] Molecular changes involve cellular signaling pathways and mitochondria-related DNA. […] The cellular origin of HCC, as well as other thyroid cancer types, is still not completely understood. […] The high prevalence of Hrthle cell changing into thyroid lesions may reflect high oxidative stress and reactive oxygen species production in thyroid cells during normal iodine and thyroid hormone metabolism.

• #28 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7793513/

  These high reactive oxygen species levels can result in mutagenic genetic events in mitochondrial DNA, leading to mitochondrial dysfunction. […] Abnormality of mitochondria leads to defects in the energy production process, and a compensatory mechanism for these defects is considered to come into play. […] This results in increased proliferation of numerous mitochondria, which is observed as oncocytic cytoplasm. […] Over time, as the number of the mitochondria increases, Hrthle cell appearance is expressed, and this is a continuous process rather than a black-and-white phenomenon. […] In cases of HCC, necrosis frequently appears either spontaneously or after fine-needle aspiration. […] The genetic profile of HCC differs from papillary thyroid carcinoma and follicular thyroid carcinoma.

• #29 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7793513/

  These high reactive oxygen species levels can result in mutagenic genetic events in mitochondrial DNA, leading to mitochondrial dysfunction. […] Abnormality of mitochondria leads to defects in the energy production process, and a compensatory mechanism for these defects is considered to come into play. […] This results in increased proliferation of numerous mitochondria, which is observed as oncocytic cytoplasm. […] Over time, as the number of the mitochondria increases, Hrthle cell appearance is expressed, and this is a continuous process rather than a black-and-white phenomenon. […] In cases of HCC, necrosis frequently appears either spontaneously or after fine-needle aspiration. […] The genetic profile of HCC differs from papillary thyroid carcinoma and follicular thyroid carcinoma.

• #30 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7793513/

  These high reactive oxygen species levels can result in mutagenic genetic events in mitochondrial DNA, leading to mitochondrial dysfunction. […] Abnormality of mitochondria leads to defects in the energy production process, and a compensatory mechanism for these defects is considered to come into play. […] This results in increased proliferation of numerous mitochondria, which is observed as oncocytic cytoplasm. […] Over time, as the number of the mitochondria increases, Hrthle cell appearance is expressed, and this is a continuous process rather than a black-and-white phenomenon. […] In cases of HCC, necrosis frequently appears either spontaneously or after fine-needle aspiration. […] The genetic profile of HCC differs from papillary thyroid carcinoma and follicular thyroid carcinoma.

• #31 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7793513/

  Molecular pathways that differentiate Hrthle cell adenoma from HCC with wide invasiveness included the PIK3CA-Akt-mTOR and Wnt, providing rationale toward new targets of this type of malignancy. […] A significant difference in oncogene expression between follicular thyroid carcinoma (FTC) and HCC suggests that despite having a common origin in the follicular cell, follicular thyroid carcinoma and HCC should be considered as two separate entities. […] HCC shows changes in both nuclear DNA and mitochondrial DNA (mtDNA). […] Mitochondrial genetic changes involve interaction between mutations in the mitochondrial and nuclear genomes. […] The mitochondrial DNA (mtDNA) is small, and incorporates a sequence of 16,569 bp, encoding 13 essential components in cellular energy production. […] Mitochondrial DNA (mtDNA) is more susceptible than nuclear DNA to mutagen-induced damage. […] Disruptive mutations in mitochondrial DNA are found in complex I subunit genes in Hrthle cell tumors. […] Mitochondrial mutations may play a part as one of many factors leading to tumor development.

• #32 The Molecular Landscape of Hürthle Cell Thyroid Cancer Is Associated with Altered Mitochondrial Function—A Comprehensive Review

  https://www.mdpi.com/2073-4409/9/7/1570

  The dysregulated mitochondrial function leading to excessive ROS production and downregulated OXPHOS which has been observed in HTC is associated with the compensatory upregulation of aerobic glycolysis. […] Overactive PI3K/AKT/mTOR signaling in HTC is associated with increased glycolysis as a major source of energy production. […] The enhanced glucose uptake and increased glycolysis of HTC cells has been translated to the clinical setting and used for diagnostic and prognostic purposes through functional imaging relying on radiolabeled glucose uptake in HTC metastases.

• #33 Oncocytic (Hürthle Cell) Thyroid Carcinoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK568736/

  Oncocytic carcinoma, previously known as Hrthle cell carcinoma, is a rare type of thyroid cancer originating from oncocytic cells, a specialized type of follicular thyroid cell. These cells are identified by their eosinophilic cytoplasm and an abundance of granular cytoplasm. Until 2022, oncocytic carcinoma was considered a variant of follicular thyroid carcinoma, but it has since been reclassified as a separate subtype by the World Health Organization (WHO). Oncocytic thyroid carcinoma’s distinct histopathological features and molecular differences, particularly mutations in the mitochondrial genome and gene expression profiles, set it apart from follicular thyroid carcinoma.[1] […] Various genetic, environmental, and biological factors influence the development of oncocytic thyroid cancer. This type of cancer originates from specialized follicular thyroid cells called oncocytes, characterized by their abundant eosinophilic cytoplasm and high mitochondrial content. The pathogenesis of oncocytic cancer is associated with specific genetic mutations, particularly in mitochondrial DNA, and changes in nuclear genes. Mutations in oncogenes like BRAF and HRAS and inactivation of tumor suppressor genes (eg, PTEN) have been identified, indicating a disruption of normal cellular signaling pathways that control cell growth and survival.[2]

• #34 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7793513/

  Molecular pathways that differentiate Hrthle cell adenoma from HCC with wide invasiveness included the PIK3CA-Akt-mTOR and Wnt, providing rationale toward new targets of this type of malignancy. […] A significant difference in oncogene expression between follicular thyroid carcinoma (FTC) and HCC suggests that despite having a common origin in the follicular cell, follicular thyroid carcinoma and HCC should be considered as two separate entities. […] HCC shows changes in both nuclear DNA and mitochondrial DNA (mtDNA). […] Mitochondrial genetic changes involve interaction between mutations in the mitochondrial and nuclear genomes. […] The mitochondrial DNA (mtDNA) is small, and incorporates a sequence of 16,569 bp, encoding 13 essential components in cellular energy production. […] Mitochondrial DNA (mtDNA) is more susceptible than nuclear DNA to mutagen-induced damage. […] Disruptive mutations in mitochondrial DNA are found in complex I subunit genes in Hrthle cell tumors. […] Mitochondrial mutations may play a part as one of many factors leading to tumor development.

• #35 The Molecular Landscape of Hürthle Cell Thyroid Cancer Is Associated with Altered Mitochondrial Function—A Comprehensive Review

  https://www.mdpi.com/2073-4409/9/7/1570

  The dysregulated mitochondrial function leading to excessive ROS production and downregulated OXPHOS which has been observed in HTC is associated with the compensatory upregulation of aerobic glycolysis. […] Overactive PI3K/AKT/mTOR signaling in HTC is associated with increased glycolysis as a major source of energy production. […] The enhanced glucose uptake and increased glycolysis of HTC cells has been translated to the clinical setting and used for diagnostic and prognostic purposes through functional imaging relying on radiolabeled glucose uptake in HTC metastases.

• #36 Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7793513/

  Molecular pathways that differentiate Hrthle cell adenoma from HCC with wide invasiveness included the PIK3CA-Akt-mTOR and Wnt, providing rationale toward new targets of this type of malignancy. […] A significant difference in oncogene expression between follicular thyroid carcinoma (FTC) and HCC suggests that despite having a common origin in the follicular cell, follicular thyroid carcinoma and HCC should be considered as two separate entities. […] HCC shows changes in both nuclear DNA and mitochondrial DNA (mtDNA). […] Mitochondrial genetic changes involve interaction between mutations in the mitochondrial and nuclear genomes. […] The mitochondrial DNA (mtDNA) is small, and incorporates a sequence of 16,569 bp, encoding 13 essential components in cellular energy production. […] Mitochondrial DNA (mtDNA) is more susceptible than nuclear DNA to mutagen-induced damage. […] Disruptive mutations in mitochondrial DNA are found in complex I subunit genes in Hrthle cell tumors. […] Mitochondrial mutations may play a part as one of many factors leading to tumor development.

• #37 Meta-analysis utilizing public data suggests role of innate immunity in the pathogenesis of hurthle cell carcinoma (HCC). – ASCO

  https://www.asco.org/abstracts-presentations/ABSTRACT270333

  Hurthle Cell Carcinoma (HCC), a variant of follicular thyroid carcinoma, is a rare form of thyroid cancer. […] very little is known about its pathogenesis. […] it is still vital to understand the pathogenesis of HCC in order to further optimize treatment protocols. […] Hepatic fibrosis, hepatic stellate cell activation and retinoic acid receptor (RAR) activation were the top canonical activators associated with HCC. […] The most down-regulated molecules were Hemoglobin Subunit Beta (HBB), Hemoglobin Subunit Alpha 1 and 2 (HBA1/HBA2), Cellular Retinoic Acid Binding Protein 1 (CRABP1), and BH3-Interacting Domain-Containing Protein 3 (HRK). […] These results suggest that there are a variety of factors at play regarding the development of HCC. […] While the exact pathogenesis of HCC is not well known yet, we demonstrate that the two most up-regulated factors in HCC are strongly involved in innate immunity. This suggests that the dysfunction of innate immunity may play a vital role in the neoplastic pathogenesis of HCC.

• #38 Metabolic reprogramming related to whole-chromosome instability in models for Hürthle cell carcinoma | Scientific Reports

  https://www.nature.com/articles/s41598-020-66599-1

  Hrthle cell carcinoma (HCC) is characterized by profound whole-chromosome instability (w-CIN), resulting in a near-homozygous genome (NHG), a phenomenon recently attributed to reactive oxygen species (ROS) generated during mitosis by malfunctioning mitochondria. […] w-CIN may be driven by factors such as increased intracellular production of reactive oxygen species (ROS) as a by-product of metabolic changes following the loss of CI functionality. […] Thus, many HCCs show a near-homozygous genome (NHG), a term that covers both a near-haploid genome status and the status after endoreduplication. […] Our data suggests that metabolic reprogramming and a subtle balance between ROS generation and scavenging/conversion of intermediates may be involved in ROS-induced w-CIN in HCC and possibly also in rare cases of follicular thyroid cancer showing a NHG.

• #39 Metabolic reprogramming related to whole-chromosome instability in models for Hürthle cell carcinoma | Scientific Reports

  https://www.nature.com/articles/s41598-020-66599-1

  Hrthle cell carcinoma (HCC) is characterized by profound whole-chromosome instability (w-CIN), resulting in a near-homozygous genome (NHG), a phenomenon recently attributed to reactive oxygen species (ROS) generated during mitosis by malfunctioning mitochondria. […] w-CIN may be driven by factors such as increased intracellular production of reactive oxygen species (ROS) as a by-product of metabolic changes following the loss of CI functionality. […] Thus, many HCCs show a near-homozygous genome (NHG), a term that covers both a near-haploid genome status and the status after endoreduplication. […] Our data suggests that metabolic reprogramming and a subtle balance between ROS generation and scavenging/conversion of intermediates may be involved in ROS-induced w-CIN in HCC and possibly also in rare cases of follicular thyroid cancer showing a NHG.

• #40 Metabolic reprogramming related to whole-chromosome instability in models for Hürthle cell carcinoma | Scientific Reports

  https://www.nature.com/articles/s41598-020-66599-1

  Hrthle cell carcinoma (HCC) is characterized by profound whole-chromosome instability (w-CIN), resulting in a near-homozygous genome (NHG), a phenomenon recently attributed to reactive oxygen species (ROS) generated during mitosis by malfunctioning mitochondria. […] w-CIN may be driven by factors such as increased intracellular production of reactive oxygen species (ROS) as a by-product of metabolic changes following the loss of CI functionality. […] Thus, many HCCs show a near-homozygous genome (NHG), a term that covers both a near-haploid genome status and the status after endoreduplication. […] Our data suggests that metabolic reprogramming and a subtle balance between ROS generation and scavenging/conversion of intermediates may be involved in ROS-induced w-CIN in HCC and possibly also in rare cases of follicular thyroid cancer showing a NHG.

• #41 Metabolic reprogramming related to whole-chromosome instability in models for Hürthle cell carcinoma | Scientific Reports

  https://www.nature.com/articles/s41598-020-66599-1

  This mechanism may be regulated via enhanced CHK2 phosphorylation, as seen in mitotic cells after AMA treatment, which could in turn contribute to lagging chromosomes and missegregation. […] Our data points to a subtle balance between ROS generation and scavenging, directly via creatine and/or -KG and/or conversion of ROS intermediates.

• #42 Meta-analysis utilizing public data suggests role of innate immunity in the pathogenesis of hurthle cell carcinoma (HCC). – ASCO

  https://www.asco.org/abstracts-presentations/ABSTRACT270333

  Hurthle Cell Carcinoma (HCC), a variant of follicular thyroid carcinoma, is a rare form of thyroid cancer. […] very little is known about its pathogenesis. […] it is still vital to understand the pathogenesis of HCC in order to further optimize treatment protocols. […] Hepatic fibrosis, hepatic stellate cell activation and retinoic acid receptor (RAR) activation were the top canonical activators associated with HCC. […] The most down-regulated molecules were Hemoglobin Subunit Beta (HBB), Hemoglobin Subunit Alpha 1 and 2 (HBA1/HBA2), Cellular Retinoic Acid Binding Protein 1 (CRABP1), and BH3-Interacting Domain-Containing Protein 3 (HRK). […] These results suggest that there are a variety of factors at play regarding the development of HCC. […] While the exact pathogenesis of HCC is not well known yet, we demonstrate that the two most up-regulated factors in HCC are strongly involved in innate immunity. This suggests that the dysfunction of innate immunity may play a vital role in the neoplastic pathogenesis of HCC.

• #43 Researchers Uncover Clues to Treating Rare Thyroid Cancer

  https://consultqd.clevelandclinic.org/researchers-uncover-clues-to-treating-rare-thyroid-cancer

  Tumors that had a global loss of heterozygosity (LOH) had very low levels of immune infiltration, which may indicate a low probability of responding to immunotherapy. […] HCC behaves differently on a molecular level in comparison other thyroid cancers and must be treated differently, says Dr. Chan.

• #44 Concurrence of Papillary Thyroid Carcinoma and Hürthle Cell Carcinoma in an Iranian Woman with Hashimoto’s Thyroiditis

  https://ijp.iranpath.org/article_36557.html

  The most usual form of the endocrine carcinoma is thyroid cancer (TC). […] Recent studies revealed incidence of RET/PTC rearrangement in other tumors, like Hrthle cell carcinoma (HCC) and even in non-carcinomatous disorders like Hashimoto’s thyroiditis. […] Concurrence of papillary carcinoma and Hrthle cell carcinoma is a rare form of thyroid malignancies, with doubtful cytogenetic findings and biological behaviors. […] The continuous and persistent inflammatory reaction causes cell injury via reactive oxygen species generation (ROS). DNA damaging by ROS causes various mutations that some of them lead to the creation of thyroid malignancy. […] A recent research has shown RET/PTC rearrangement in other tumors like HCC and even in non-carcinomatous disorders like Hashimoto’s thyroiditis.

• #45 Concurrence of Papillary Thyroid Carcinoma and Hürthle Cell Carcinoma in an Iranian Woman with Hashimoto’s Thyroiditis

  https://ijp.iranpath.org/article_36557.html

  The most usual form of the endocrine carcinoma is thyroid cancer (TC). […] Recent studies revealed incidence of RET/PTC rearrangement in other tumors, like Hrthle cell carcinoma (HCC) and even in non-carcinomatous disorders like Hashimoto’s thyroiditis. […] Concurrence of papillary carcinoma and Hrthle cell carcinoma is a rare form of thyroid malignancies, with doubtful cytogenetic findings and biological behaviors. […] The continuous and persistent inflammatory reaction causes cell injury via reactive oxygen species generation (ROS). DNA damaging by ROS causes various mutations that some of them lead to the creation of thyroid malignancy. […] A recent research has shown RET/PTC rearrangement in other tumors like HCC and even in non-carcinomatous disorders like Hashimoto’s thyroiditis.

• #46 Concurrence of Papillary Thyroid Carcinoma and Hürthle Cell Carcinoma in an Iranian Woman with Hashimoto’s Thyroiditis

  https://ijp.iranpath.org/article_36557.html

  The prognosis of patients with concurrent thyroid carcinoma and HT is better than that of patients with thyroid carcinoma alone. […] Collision tumors that are complex of some tumors apart have been detected in different organs except thyroid. […] Although, the collision tumors of the thyroid gland are rare, they have been reported as a concurrence of independent tumors in thyroid in some studies. […] The therapeutic strategies of the collision tumors should depend on the presumed primary tumors. […] Better perception of different combinations of pathologies and their effects on the prognosis and therapeutic strategies can be gained by reporting such cases and careful follow up. […] The prognosis of PTC after the surgical debulking of tumor, levothyroxine suppressive therapy, and Iodine radiotherapy are suitable.

• #47 Surgical management of metastatic Hürthle cell carcinoma to the skull base, cortex, and spine: illustrative case in: Journal of Neurosurgery: Case Lessons Volume 6 Issue 15 (2023) Journals

  https://thejns.org/caselessons/view/journals/j-neurosurg-case-lessons/6/15/article-CASE23263.xml

  Hrthle cell carcinoma (HCC) is an unusual and aggressive variant of the follicular type of differentiated thyroid cancer (DTC), accounting for less than 3% of DTCs but posing the highest risk of metastasis. […] The unique molecular pathogenesis and unpredictable biological behavior of HCC are distinct challenges in outlining and applying a definitive treatment strategy. […] The low rate of BMs from HCC coupled with ambiguous treatment protocols for the extracranial disease further complicate successful disease management. […] Hrthle cell carcinomas are oxyphilic and characterized by an abundance of dysfunctional mitochondria (75% of cell volume), unique chromosomal landscapes (responsible for their aggression), and DNA copy number alterations. […] The prognosis of HCC is predicted via investigation of tumor size, degree of infection, extrathyroidal disease extension, and initial nodal or distant metastasis.

• #48 Identification of Hürthle cell cancers: solving a clinical challenge with genomic sequencing and a trio of machine learning algorithms | BMC Systems Biology | Full Text

  https://bmcsystbiol.biomedcentral.com/articles/10.1186/s12918-019-0693-z

  Insights into Hrthle cell carcinomas are growing, with recent investigations reporting alterations in nuclear and mitochondrial genomes and enriched genomic instability, which differ from the genomic profiles of non-Hrthle neoplasms. […] We sought to identify genomic features associated with Hrthle cell positive, neoplasm positive samples. Previous reports have identified copy number changes in Hrthle subtypes. […] Interestingly, the LOH was primarily, but not exclusively, enriched in Hrthle cell carcinomas. […] We demonstrate in clinical validation a preserved high sensitivity among our Hrthle cell neoplasms when the entire system performance is considered. […] It is noteworthy that we observed significant LOH among a fraction of both histologically benign and malignant Hrthle cell neoplasms. Whether or not the genomic instability of LOH should represent a pre-malignant, or carcinoma in-situ, is unknown and their natural history is unknown since these neoplasms were all surgically resected in our training and validation cohorts.

• #49 Hürthle Cell Carcinoma of the Thyroid – Well-Differentiated Thyroid Cancer or Something Else?

  https://scholars.direct/Articles/head-and-neck-surgery/jhns-2-002.php?jid=head-and-neck-surgery

  Hürthle cell carcinoma is a rare thyroid neoplasm with unpredictable development. […] This case illustrates an aggressive Hürthle cell carcinoma with unpredictable slow progressive development and resistant to treatment options including surgery and radioactive iodine. […] Nowadays the main criteria for differentiation between benign from malignant Hürtle cell neoplasm is full-thickness capsular and/or vascular invasion. […] Hürtle cell carcinomas are known to be able to secrete thyreoglobulin but generally fail to concentrate 131 I and therefore, in most patient, radioablation does not offer a therapeutic benefit. […] However many studies have showed that Total thyroidectomy and RAI ablation of thyroid remnant tissue can impact the survival of patients. […] Although chemotherapy has proved ineffective in the past there are some initial reports that some new molecules might be an effective chemotherapy regimen for multi-metastatic of Hurthle cell carcinoma. […] Hürthle cell carcinoma is a unique and unpredictable disease.

• #50 Clinical characteristics and prognostic factors of Hurthle cell carcinoma: a population based study | BMC Cancer | Full Text

  https://bmccancer.biomedcentral.com/articles/10.1186/s12885-020-06915-0

  This result suggests that the cancer-specific prognosis of HCC is not greatly affected by surgical methods. […] Radioactive iodine (RAI) is widely used for the treatment of differentiated thyroid cancer, especially papilla thyroid carcinoma. However, HCC is insensitive to RAI due to the low iodine uptake rate. […] HCC is associated with a higher metastasis rate and a lower survival rate compared to other differentiated thyroid cancers. […] Age, tumor size, and sex are prognostic factors of HCC, and tumor extension and recurrence often indicate poor prognosis and increased mortality. […] The SEER stage is an independent prognostic factor for HCC, and distant disease is associated with significantly poor prognosis. Age over 45years, distant SEER stage, and late T-stage are independent risk factors for mortality in HCC.

• #51 Researchers Uncover Clues to Treating Rare Thyroid Cancer

  https://consultqd.clevelandclinic.org/researchers-uncover-clues-to-treating-rare-thyroid-cancer

  Hurthle cell carcinoma (HCC) is a rare type of thyroid cancer that is not responsive to standard therapies like radioactive iodine. […] Several years ago, the pair were part of a research team that published the first genomic analysis of HCC, demonstrating its unique mutations. […] Earlier studies indicated that mTOR signaling is altered in HCC, suggesting this pathway as potential therapeutic targets. […] The researchers goal is to move into larger clinical trials to validate mTOR inhibitors are as a viable treatment for HCC. […] If we can show that HCC with mTOR mutations respond well to mTOR inhibitors, it could support a future FDA indication. […] Through this work, we aim to understand the mechanisms of resistance to the drug, and understand other genomics so that we can better assess which patients will respond to treatment.

• #52 Hurthle cell carcinoma: current perspectives | OTT

  https://www.dovepress.com/huumlrthle-cell-carcinoma-current-perspectives-peer-reviewed-fulltext-article-OTT

  The finding of a HCN should prompt thorough ultrasound evaluation of all compartments of the neck prior to surgery. […] HCC is associated with more aggressive clinical behavior compared to other differentiated thyroid cancers; for example, it is more often seen with a higher rate of distant metastases.

• #53 Surgical management of metastatic Hürthle cell carcinoma to the skull base, cortex, and spine: illustrative case in: Journal of Neurosurgery: Case Lessons Volume 6 Issue 15 (2023) Journals

  https://thejns.org/caselessons/view/journals/j-neurosurg-case-lessons/6/15/article-CASE23263.xml

  A well-defined, full-fledged management protocol for HCC with BM, apart from local therapies, has yet to take shape. […] Given the poor survival rates and stagnant nature of disease management for HCC, there is an urgent need to develop new therapeutic approaches for the improved management of distant HCC metastases. […] Because of its rare incidence, metastatic HCC lacks a standardized treatment protocol. […] Presently, the best strategy typically includes combined radioactive iodine (RAI) therapy and surgery. […] While there are no systemic therapies specifically for metastatic HCC, the U.S. Food and Drug Administration has approved 2 multikinase inhibitors, sorafenib and Lenvatinib, for the treatment of RAI-refractory differentiated thyroid cancer.

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