今日の臨床サポート

甲状腺癌

著者: 小野田尚佳 隈病院 診療本部

監修: 平田結喜緒 公益財団法人 兵庫県予防医学協会 健康ライフプラザ

著者校正/監修レビュー済:2022/08/31
参考ガイドライン:
  1. 日本内分泌外科学会・日本甲状腺外科学会:甲状腺腫瘍診療ガイドライン2018
  1. 日本頭頸部癌学会:頭頸部癌診療ガイドライン 2022年版 第4版
  1. 日本内分泌外科学会 甲状腺微小癌取扱い委員会:成人の甲状腺低リスク微小乳頭癌 cT1aN0M0 に対する積極的経過観察の適応と方法: 日本内分泌外科学会 甲状腺微小癌取扱い委員会 による提言
患者向け説明資料

概要・推奨   

  1. 甲状腺癌の診療には、甲状腺腫瘍診療ガイドライン2018(日本内分泌外科学会・日本甲状腺外科学会)と、頭頸部癌診療ガイドライン 2022年版 第4版(日本頭頸部癌学会)の2つのガイドラインが存在する。両者の記述は基本的に同様である。
  1. 甲状腺腫瘍診療ガイドラインは、日本と海外の甲状腺診療の違いを踏まえて(治療の項コラム参照:)、わが国独自の治療アルゴリズムの確立を目指し、病期分類も本邦の甲状腺癌取扱い規約に依っている。
  1. 頭頸部癌診療ガイドラインの病期分類は国際基準の記載方法に依っており、内容は上記の甲状腺腫瘍診療ガイドラインだけでなく、海外のガイドライン(米国甲状腺学会ガイドライン、NCCN(National Comprehensive Cancer Network))の内容を広く紹介している。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
小野田尚佳 : 特に申告事項無し[2022年]
監修:平田結喜緒 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 甲状腺腫瘍診療ガイドライン2018、頭頸部癌診療ガイドライン 2022年版などに基づき、執筆した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. わが国における甲状腺癌罹患数は増加している。2018年における甲状腺癌診断数は18,636人、うち男性4,790人、女性13,846人で、男女比は1:2.9と女性に多い。2019年における甲状腺癌による死亡数は1,862人、うち男性619人、女性1,243人[1]
  1. 米国では1975年から2009年の34年間に甲状腺癌罹患率が4.9人/10万人から14.3人/10万人と2.9倍に増加したが、死亡率は0.5人/10万人と変化がなかった[2]。濾胞癌、髄様癌、未分化癌の増加はなく、乳頭癌の中でも2cm以下の癌のみが増加していた[3]。この結果から、無症候性の小さい乳頭癌の診断が増加していることが明らかで、全世界的に同様の傾向が示されている。2000年代初頭に、甲状腺癌が急激に増加したとの疫学的観察があったが、検診の増加に伴う発見頻度の増加であった[4]
  1. 小児期の放射線被曝は、甲状腺癌の明らかなリスク因子である[5]。旧ソビエトの原子力発電所事故後に小児の甲状腺癌の罹患が増加した[6]。福島の原子力発電所事故後調査は続行中であるが、これまで甲状腺癌罹患者が増加したという報告はない[7]
 
病理組織分類:
  1. 甲状腺癌は、組織学的形態により乳頭癌、濾胞癌、低分化癌、未分化癌、髄様癌に分類する。甲状腺原発の非上皮性悪性腫瘍には、慢性甲状腺炎を背景として発生するリンパ腫がある。その他の組織型が発生する頻度は極めて少ない[8]
  1. ヨウ素摂取量が少ない地域では濾胞癌が多く、摂取量が多い地域では乳頭癌が多い。ヨウ素摂取の多いわが国では甲状腺悪性腫瘍の90%以上が乳頭癌、約5%が濾胞癌であり、低分化癌、未分化癌、髄様癌、リンパ腫がそれぞれ1~2%である。
  1. 甲状腺癌は病理組織型によって遺伝子変異、臨床像、治療法、予後が大きく異なる。
 
甲状腺癌の病理組織型別特徴

出典

img1:  著者提供
 
 
各病理組織型の特徴  
乳頭癌:
  1. 濾胞上皮に由来し、最も多いタイプ(>90%)で、進行は緩徐。腫瘤径1cm以下を微小乳頭癌と称し、後述するように非手術経過観察の対象となり得る。(微小乳頭癌の非手術経過観察についての項参照: >詳細情報 )

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文献 

Louise Davies, H Gilbert Welch
Increasing incidence of thyroid cancer in the United States, 1973-2002.
JAMA. 2006 May 10;295(18):2164-7. doi: 10.1001/jama.295.18.2164.
Abstract/Text CONTEXT: Increasing cancer incidence is typically interpreted as an increase in the true occurrence of disease but may also reflect changing pathological criteria or increased diagnostic scrutiny. Changes in the diagnostic approach to thyroid nodules may have resulted in an increase in the apparent incidence of thyroid cancer.
OBJECTIVE: To examine trends in thyroid cancer incidence, histology, size distribution, and mortality in the United States.
METHODS: Retrospective cohort evaluation of patients with thyroid cancer, 1973-2002, using the Surveillance, Epidemiology, and End Results (SEER) program and data on thyroid cancer mortality from the National Vital Statistics System.
MAIN OUTCOME MEASURES: Thyroid cancer incidence, histology, size distribution, and mortality.
RESULTS: The incidence of thyroid cancer increased from 3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2002-a 2.4-fold increase (95% confidence interval [CI], 2.2-2.6; P<.001 for trend). There was no significant change in the incidence of the less common histological types: follicular, medullary, and anaplastic (P>.20 for trend). Virtually the entire increase is attributable to an increase in incidence of papillary thyroid cancer, which increased from 2.7 to 7.7 per 100,000-a 2.9-fold increase (95% CI, 2.6-3.2; P<.001 for trend). Between 1988 (the first year SEER collected data on tumor size) and 2002, 49% (95% CI, 47%-51%) of the increase consisted of cancers measuring 1 cm or smaller; 87% (95% CI, 85%-89%) consisted of cancers measuring 2 cm or smaller. Mortality from thyroid cancer was stable between 1973 and 2002 (approximately 0.5 deaths per 100,000).
CONCLUSIONS: The increasing incidence of thyroid cancer in the United States is predominantly due to the increased detection of small papillary cancers. These trends, combined with the known existence of a substantial reservoir of subclinical cancer and stable overall mortality, suggest that increasing incidence reflects increased detection of subclinical disease, not an increase in the true occurrence of thyroid cancer.

PMID 16684987
Salvatore Vaccarella, Silvia Franceschi, Freddie Bray, Christopher P Wild, Martyn Plummer, Luigino Dal Maso
Worldwide Thyroid-Cancer Epidemic? The Increasing Impact of Overdiagnosis.
N Engl J Med. 2016 Aug 18;375(7):614-7. doi: 10.1056/NEJMp1604412.
Abstract/Text
PMID 27532827
E Ron, J H Lubin, R E Shore, K Mabuchi, B Modan, L M Pottern, A B Schneider, M A Tucker, J D Boice
Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies.
Radiat Res. 1995 Mar;141(3):259-77.
Abstract/Text The thyroid gland of children is especially vulnerable to the carcinogenic action of ionizing radiation. To provide insights into various modifying influences on risk, seven major studies with organ doses to individual subjects were evaluated. Five cohort studies (atomic bomb survivors, children treated for tinea capitis, two studies of children irradiated for enlarged tonsils, and infants irradiated for an enlarged thymus gland) and two case-control studies (patients with cervical cancer and childhood cancer) were studied. The combined studies include almost 120,000 people (approximately 58,000 exposed to a wide range of doses and 61,000 nonexposed subjects), nearly 700 thyroid cancers and 3,000,000 person years of follow-up. For persons exposed to radiation before age 15 years, linearity best described the dose response, even down to 0.10 Gy. At the highest doses (> 10 Gy), associated with cancer therapy, there appeared to be a decrease or leveling of risk. For childhood exposures, the pooled excess relative risk per Gy (ERR/Gy) was 7.7 (95% CI = 2.1, 28.7) and the excess absolute risk per 10(4) PY Gy (EAR/10(4) PY Gy) was 4.4 (95% CI = 1.9, 10.1). The attributable risk percent (AR%) at 1 Gy was 88%. However, these summary estimates were affected strongly by age at exposure even within this limited age range. The ERR was greater (P = 0.07) for females than males, but the findings from the individual studies were not consistent. The EAR was higher among women, reflecting their higher rate of naturally occurring thyroid cancer. The distribution of ERR over time followed neither a simple multiplicative nor an additive pattern in relation to background occurrence. Only two cases were seen within 5 years of exposure. The ERR began to decline about 30 years after exposure but was still elevated at 40 years. Risk also decreased significantly with increasing age at exposure, with little risk apparent after age 20 years. Based on limited data, there was a suggestion that spreading dose over time (from a few days to > 1 year) may lower risk, possibly due to the opportunity for cellular repair mechanisms to operate. The thyroid gland in children has one of the highest risk coefficients of any organ and is the only tissue with convincing evidence for risk about 1.10 Gy.

PMID 7871153
Akira Ohtsuru, Sanae Midorikawa, Tetsuya Ohira, Satoru Suzuki, Hideto Takahashi, Michio Murakami, Hiroki Shimura, Takashi Matsuzuka, Seiji Yasumura, Shin-Ichi Suzuki, Susumu Yokoya, Yuko Hashimoto, Akira Sakai, Hitoshi Ohto, Shunichi Yamashita, Koichi Tanigawa, Kenji Kamiya
Incidence of Thyroid Cancer Among Children and Young Adults in Fukushima, Japan, Screened With 2 Rounds of Ultrasonography Within 5 Years of the 2011 Fukushima Daiichi Nuclear Power Station Accident.
JAMA Otolaryngol Head Neck Surg. 2019 Jan 1;145(1):4-11. doi: 10.1001/jamaoto.2018.3121.
Abstract/Text Importance: Ultrasonographic (US) screening for thyroid cancer was performed in the Fukushima Health Management Survey after the 2011 Fukushima Daiichi nuclear power station accident. Clinical characteristics of thyroid cancers screened by US among children and young adults during the first 5 years after the accident were analyzed.
Objectives: To evaluate the number of detected thyroid cancers by age group within 5 years of the Fukushima Daiichi nuclear power station accident and to compare the basic clinical characteristics and demographic patterns in first- and second-round examinations.
Design, Setting, and Participants: In this observational study, 324 301 individuals 18 years or younger at the time of accident were included. Patients received a cytologic diagnosis of malignant or suspected malignant thyroid cancer during the first (fiscal years 2011-2013) or second round (fiscal years 2014-2015) of screening. Number of detected cases of cancer was evaluated, correcting for the number of examinees by age group at the time of the accident and for the incidence of detected cancers according to age group at the time of the screening (age groups were divided into 3-year intervals). Results were compared using the age-specific incidence of unscreened cancers from a national cancer registry.
Main Outcomes and Measures: Clinical baseline characteristics of the patients and the age-specific number and incidence of thyroid cancers detected during the second round.
Results: Among 299 905 individuals screened in the first round (50.5% male; mean [SD] age at screening, 14.9 [2.6] years), malignant or suspected thyroid cancer was diagnosed in 116. Among 271 083 individuals screened in the second round (50.4% male; age at screening, 12.6 [3.2] years), malignant or suspected thyroid cancer was diagnosed in 71. The most common pathologic diagnosis in surgical cases was papillary thyroid cancer (149 of 152 [98.0%]). The distribution pattern by age group at the time of the accident, where the number of detected thyroid cancer cases was corrected by the number of examinees, increased with older age in both screening rounds. This demographic pattern was similar between the first and second examinations. The distribution pattern of the incidence rate by age group at the time of screening in the second round also increased with older age. The incidence rate detected by screening was 29 cases per 100 000 person-years for those aged 15 to 17 years, 48 cases per 100 000 person-years for those aged 18 to 20 years, and 64 cases per 100 000 person-years for those aged 21 to 22 years.
Conclusions and Relevance: Large-scale mass US screening of young people resulted in the diagnosis of a number of thyroid cancers, with no major changes in overall characteristics within 5 years of the 2011 Fukushima nuclear power station accident. These results suggest that US screening can identify many detectable cancers from a large pool of nonclinical and subclinical thyroid cancers among individuals of a relatively young age, in an age-dependent manner.

PMID 30489622
Young Shin Song, Jung Ah Lim, Young Joo Park
Mutation Profile of Well-Differentiated Thyroid Cancer in Asians.
Endocrinol Metab (Seoul). 2015 Sep;30(3):252-62. doi: 10.3803/EnM.2015.30.3.252.
Abstract/Text Recent advances in molecular diagnostics have led to significant insights into the genetic basis of thyroid tumorigenesis. Among the mutations commonly seen in thyroid cancers, the vast majority are associated with the mitogen-activated protein kinase pathway. B-Raf proto-oncogene (BRAF) mutations are the most common mutations observed in papillary thyroid cancers (PTCs), followed by RET/PTC rearrangements and RAS mutations, while follicular thyroid cancers are more likely to harbor RAS mutations or PAX8/peroxisome proliferator-activated receptor γ (PPARγ) rearrangements. Beyond these more common mutations, alterations in the telomerase reverse transcriptase (TERT) promoter have recently been associated with clinicopathologic features, disease prognosis, and tumorigenesis in thyroid cancer. While the mutations underlying thyroid tumorigenesis are well known, the frequency of these mutations is strongly associated with geography, with clear differences reported between Asian and Western countries. Of particular interest is the prevalence of BRAF mutations, with Korean patients exhibiting the highest rate of BRAF-associated thyroid cancers in the world. Here, we review the prevalence of each of the most common mutations in Asian and Western countries, and identify the characteristics of well-differentiated thyroid cancer in Asians.

PMID 26435130
Cancer Genome Atlas Research Network
Integrated genomic characterization of papillary thyroid carcinoma.
Cell. 2014 Oct 23;159(3):676-90. doi: 10.1016/j.cell.2014.09.050.
Abstract/Text Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.

PMID 25417114
Libero Santarpia, Jeffrey N Myers, Steven I Sherman, Francesco Trimarchi, Gary L Clayman, Adel K El-Naggar
Genetic alterations in the RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways in the follicular variant of papillary thyroid carcinoma.
Cancer. 2010 Jun 15;116(12):2974-83. doi: 10.1002/cncr.25061.
Abstract/Text BACKGROUND: The follicular variant of papillary thyroid carcinoma (FVPTC) is the second most common histotype among papillary thyroid cancers (PTCs). Although the prognosis of FVPTC is similar to the conventional phenotype, differential diagnostic difficulties may not be uncommon with other follicular thyroid neoplasms, and little is known about their genetic alterations. Defining these alterations may lead to the identification of diagnostic and biologic markers.
METHODS: In this study, the authors evaluated genetic alterations and downstream-activated signals of the Ras/Raf-mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene (Akt) (PI3K/Akt) signaling pathways in 30 FVPTC tissue specimens. Tumors and matched normal thyroid samples were tested for RAS, for the v-raf murine sarcoma viral oncogene (BRAF) substitution of valine (V) for glutamate (E) at codon 600 (the V600E mutation), for phosphatase and tensin homolog (PTEN), for catalytic PI3k p110 subunit alpha (PIK3CA), for AKT, and for the presence of rearranged during transfection (ret) proto-oncogene/PTC (RET-PTC) and paired box-8 (PAX8)/peroxisome proliferator-activated receptor gamma (PPARgamma) fusion protein (PAX8-PPARgamma) rearrangements by direct sequencing and reverse transcriptase-polymerases chain reaction analyses, respectively. Western blot analysis was used to assess the effects of these gene abnormalities on the activation of the 2 pathways.
RESULTS: Genetic alterations were identified in 70% of FVPTCs. Activation of the MAPK and PI3K pathways was observed in 74% and 22% of tumors, respectively. The alterations that were identified in the genes of the 2 pathways were mutually exclusive. Chromosomal RET-PTC and PAX8-PPARgamma rearrangements were observed in 20% and 17% of tumors, respectively. It was noteworthy that some FVPTCs with RET-PTC had the coactivation of both pathways.
CONCLUSIONS: RET-PTC and PAX8-PPARgamma rearrangements and mutations of the neuroblastoma RAS viral oncogene homolog N-RAS at codon 61 were the most common genetic alterations in FVPTCs. Activation of the MAPK pathway was a frequent event in FVPTCs, and the PI3K signaling pathway could be coactivated in RET-PTC tumors. These findings may have important therapeutic implication in patients with FVPTC.

PMID 20564403
Zubair W Baloch, Virginia A LiVolsi, Syl L Asa, Juan Rosai, Maria J Merino, Gregory Randolph, Philippe Vielh, Richard M DeMay, Mary K Sidawy, William J Frable
Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference.
Diagn Cytopathol. 2008 Jun;36(6):425-37. doi: 10.1002/dc.20830.
Abstract/Text The National Cancer Institute (NCI) sponsored the NCI Thyroid Fine-needle Aspiration (FNA) State of the Science Conference on October 22-23, 2007 in Bethesda, MD. The two-day meeting was accompanied by a permanent informational website and several on-line discussion periods between May 1 and December 15, 2007 (http://thyroidfna.cancer.gov). This document summarizes matters regarding diagnostic terminology/classification scheme for thyroid FNA interpretation and cytomorphologic criteria for the diagnosis of various benign and malignant thyroid lesions. (http://thyroidfna.cancer.gov/pages/info/agenda/).

PMID 18478609
Iwao Sugitani, Nobukatsu Kasai, Yoshihide Fujimoto, Akio Yanagisawa
A novel classification system for patients with PTC: addition of the new variables of large (3 cm or greater) nodal metastases and reclassification during the follow-up period.
Surgery. 2004 Feb;135(2):139-48. doi: 10.1016/S0039.
Abstract/Text BACKGROUND: Several factors have been proven to be useful for classifying patients with papillary thyroid carcinoma (PTC) into either low- or high-risk groups. However, the relative importance of prognostic factors, including lymph nodal metastasis, remains unclear.
METHODS: A total of 604 patients who underwent initial surgery for PTC (diameter of tumor>1 cm) were analyzed. The mean duration of follow-up was 10.7 years.
RESULTS: By multivariate analysis for disease-specific survival, distant metastasis was the only significant risk factor (risk ratio=65.1) for younger patients (age<50). For older patients (age> or =50), distant metastasis (risk ratio=6.7), extrathyroidal invasion (risk ratio=2.4), and large nodal metastasis (> or =3 cm; risk ratio=5.3) had relative importance. From the results, younger patients with distant metastasis and older patients with any of the 3 factors were defined as at high risk, whereas the other patients were defined as at low risk. Overall, 106 patients at high risk (18%) and 498 patients at low risk (83%) had 10-year survival rates of 69% and 99%, respectively. Only 3 patients of the low-risk group died from the disease. Among postoperative factors, recurrence within 3 years after initial surgery was the most important risk factor for cancer death. Of the high-risk group, patients with a disease-free interval of >3 years showed an excellent outcome (96% of a 10-year survival rate), similar to patients in the low-risk group.
CONCLUSIONS: A novel classification system, in which large nodal metastases and postoperative reclassification were added, was devised. This was useful for choosing proper therapeutic strategies, offering rational information, and determining adequate postoperative follow-up schemes for individual patients with PTC.

PMID 14739848
Yasuhiro Ito, Kiyoshi Ichihara, Hiroo Masuoka, Mitsuhiro Fukushima, Hiroyuki Inoue, Minoru Kihara, Chisato Tomoda, Takuya Higashiyama, Yuuki Takamura, Kaoru Kobayashi, Akihiro Miya, Akira Miyauchi
Establishment of an intraoperative staging system (iStage) by improving UICC TNM classification system for papillary thyroid carcinoma.
World J Surg. 2010 Nov;34(11):2570-80. doi: 10.1007/s00268-010-0710-2.
Abstract/Text BACKGROUND: Papillary thyroid carcinoma generally has an indolent nature, but cases demonstrating certain features are progressive. UICC TNM classification is the most widely adopted system to evaluate the biological behavior of this carcinoma, but it is doubtful whether this system that evaluates only the preoperative findings can appropriately reflect patient prognosis. In this study, we established a new staging system (iStage) based on not only preoperative but also intraoperative findings.
METHODS: We investigated the prognoses of 5,911 patients with papillary carcinoma without distant metastasis at diagnosis who underwent initial surgery between January 1987 and January 2005 and compared the utility of iStage with that of conventional classification systems, such as UICC Stage, MACIS score (>7 and ≤7), AMES, and CIH classification.
RESULTS: Disease-free survival (DFS) and cause-specific survival (CSS) of patients with stage IVA were better than those of high-risk patients on other systems, and CSS of stage III patients did not differ from stage IVA patients. We established iStage by improving the original UICC stage. We set cutoff age to 55 years, instead of 45. Patients showing significant, not minimal, extrathyroid extension on intraoperative findings underwent T upgrading: tumor size 2 cm or smaller to T3 and larger than 2 cm to T4a. N classification was revised based on the size of node metastasis and extranodal tumor extension: N0, no preoperatively detected regional node metastasis; N1, preoperatively detected regional node metastasis measuring 3 cm or less and without extranodal tumor extension on intraoperative findings; N2, regional node metastasis >3 cm or having extranodal tumor extension on intraoperative examination. Five-year and 10-year DFS and CSS of iStage IVA patients were worse than high-risk patients on other classification systems, and iStage III patients showed a worse DFS, but not CSS, than iStage I or II patients.
CONCLUSIONS: We established a new classification system, iStage, based not only on preoperative but also on intraoperative findings, which has high utility. Appropriate intraoperative evaluation is mandatory to grade biological characteristics, including prognosis, of papillary carcinoma.

PMID 20625728
Mona M Sabra, Ronald Ghossein, R Michael Tuttle
Time Course and Predictors of Structural Disease Progression in Pulmonary Metastases Arising from Follicular Cell-Derived Thyroid Cancer.
Thyroid. 2016 Apr;26(4):518-24. doi: 10.1089/thy.2015.0395. Epub 2016 Feb 12.
Abstract/Text BACKGROUND: With the advent of molecular targeted therapy for the management of radioactive iodine (RAI) refractory, progressive metastatic thyroid cancer, it becomes important to define the time course and risk factors for structural disease progression in follicular cell-derived thyroid cancer (FCDTC) patients. This will help in defining the optimal time to start these therapies and better define their impact on structural disease progression.
OBJECTIVES: This retrospective review of 199 consecutive patients with FCDTC presenting with lung metastasis examined the progression-free survival (PFS) in thyroid cancer patients with lung metastasis treated with surgery and RAI, and who had not received molecular targeted therapy or chemotherapy.
RESULTS: The median overall survival (OS) was 10.45 years, while the median PFS was 3.65 years. A strong correlation was found between OS and PFS. PFS is shorter in patients with RAI refractory disease, poorly differentiated/Hürthle cell histologies, male sex, fluorodeoxyglucose-avid metastatic foci, older age (>45 years), and pulmonary metastases >1 cm. At final follow-up (a median of 6.9 years from lung metastasis diagnosis), 68% of the patients had progressed and 46% had died.
CONCLUSIONS: With the exception of younger patients with low disease burden, most patients presenting with lung metastasis from FCDTC (RAI avid and RAI refractory) using standard-of-care approaches will have disease progression on long-term follow-up. Additional studies are needed to identify novel therapies that would improve the PFS of such patients.

PMID 26872102
Yasuhiro Ito, Mitsuyoshi Hirokawa, Takuya Higashiyama, Yuuki Takamura, Akihiro Miya, Kaoru Kobayashi, Fumio Matsuzuka, Kanji Kuma, Akira Miyauchi
Prognosis and prognostic factors of follicular carcinoma in Japan: importance of postoperative pathological examination.
World J Surg. 2007 Jul;31(7):1417-24. doi: 10.1007/s00268-007-9095-2.
Abstract/Text BACKGROUND: Follicular carcinoma is known to show a worse prognosis than papillary carcinoma because of distant metastasis in higher incidence. However, few studies have been published regarding the prognosis of follicular carcinoma patients in Japan, which prompted us to investigate this issue.
METHODS: We examined the prognosis and whether and how various clinicopathological features have affected disease-free survival (DFS) and cause-specific survival (CSS) of 334 patients who underwent initial surgery for follicular carcinoma.
RESULTS: In 18 patients (5.4%), curative surgery could not be achieved because of distant metastasis at surgery in 17 patients and local extension in 1 patient. For 316 patients who underwent curative surgery, 5-year and 10-year DFS rates were 88.4% and 75.3%, respectively. Poorly differentiated carcinoma and widely invasive carcinoma, together with some conventional prognostic factors, predicted poorer DFS of patients. On multivariate analysis, poorly differentiated carcinoma was an independent prognostic factor for DFS. The 5-year and 10-year CSS rates for these 334 patients were 96.4% and 90.4%, respectively. Curative surgery and poorly differentiated carcinoma were recognized as independent prognostic factors.
CONCLUSIONS: We can hypothesize that follicular carcinoma in Japan is generally a nonaggressive disease with a good prognosis. However, because poorly differentiated or widely invasive carcinomas showed a worse prognosis, postoperative pathological examination is important in predicting patient prognosis.

PMID 17534542
Yasuhiro Ito, Mitsuhiro Hirokawa, Makoto Fujishima, Hiroo Masuoka, Takuya Higashiyama, Minoru Kihara, Naoyoshi Onoda, Akihiro Miya, Akira Miyauchi
Prognostic significance of vascular invasion and cell-proliferation activity in widely invasive follicular carcinoma of the thyroid.
Endocr J. 2021 Aug 28;68(8):881-888. doi: 10.1507/endocrj.EJ21-0064. Epub 2021 Mar 20.
Abstract/Text Widely invasive follicular thyroid carcinoma (wi-FTC) is regarded as having an aggressive character and a dire prognosis, but it has not been known whether all wi-FTCs have a dire prognosis. Herein we retrospectively analyzed the cases of 133 patients with wi-FTCs to determine the prognostic significance of vascular invasion and cell-proliferation activity based on the Ki-67 labeling index (LI). Of the 119 patients without distant metastasis (M0), 11 (9.2%) showed recurrence during the postoperative follow-up. In a univariate analysis, the recurrence-free survival (RFS) rates of the M0 patients with vascular invasion and those with a Ki-67 LI ≥5% were significantly poorer (p = 0.0013 and p = 0.0268, respectively) than those of the patients without vascular invasion or with a Ki-67 LI <5%. Other clinicopathological factors such as patient age, gender, tumor size, and oxyphilic tumor were not significantly related to the patients' RFS. In a multivariate analysis, positive vascular invasion independently affected the RFS (p = 0.0133), but Ki-67 >5% did not (p = 0.1348). To date, only five patients have died of their thyroid carcinoma; four cases were M1. In conclusion, although M0 wi-FTC generally has a favorable prognosis, cases with positive vascular invasion or a high Ki-67 LI are likely to recur, and careful postoperative follow-up is necessary.

PMID 33746136
Abstract/Text The relationship between histologic type and survival of 258 thyroid malignancies has been analysed. A new clinicopathologic entity, poorly differentiated carcinoma of the thyroid, is proposed. Papillary and follicular carcinomas of the thyroid showed no significant difference in survival rates. Both tumors were histologically separated into well differentiated and poorly differentiated carcinomas, so that thyroid cancer, deriving from follicular cells, was divided into well differentiated, poorly differentiated, and anaplastic carcinomas. The characteristic histology of poorly differentiated carcinoma was the presence of solid, trabecular and/or scirrhous patterns. Poorly differentiated carcinoma was found in 13.6% of all thyroid malignancies, and its prognosis was worse than that of well differentiated carcinoma. The differences of survival rates among well differentiated, poorly differentiated and anaplastic carcinomas were statistically significant. Prognostic data support the suggestion that the clinicopathologic entity of poorly differentiated carcinoma is of value in determining management and survival of thyroid cancer patients.

PMID 6313176
Tihana Ibrahimpasic, Ronald Ghossein, Jatin P Shah, Ian Ganly
Poorly Differentiated Carcinoma of the Thyroid Gland: Current Status and Future Prospects.
Thyroid. 2019 Mar;29(3):311-321. doi: 10.1089/thy.2018.0509.
Abstract/Text BACKGROUND: Poorly differentiated thyroid cancer (PDTC) is a rare but clinically highly significant entity because it accounts for most fatalities from non-anaplastic follicular cell-derived thyroid cancer. Due to the relative rarity of the disease and heterogeneous diagnostic criteria, studies on PDTC have been limited. In light of the evolution of ultra-deep next-generation sequencing technologies and through correlation of clinicopathologic and genomic characteristics of PDTC, an improved understanding of the biology of PDTC has been facilitated. Here, the diagnostic criteria, clinicopathologic characteristics, management, and outcomes in PDTC, as well as genomic drivers in PDTC reported in recent next-generation sequencing studies, are reviewed. In addition, future prospects in improving the outcomes in PDTC patients are reviewed.
SUMMARY: PDTC patients tend to present with adverse clinicopathologic characteristics: older age, male predominance, advanced locoregional disease, and distant metastases. Surgery with clearance of all gross disease can achieve satisfactory locoregional control. However, the majority of PDTC patients die of distant disease. Five-year disease-specific survival for PDTC patients has been reported at 66%. On multivariate analysis, reported predictors of poor survival in PDTC patients have been older age (>45 years), T4a pathological stage, extrathyroidal extension, high mitotic rate, tumor necrosis, and distant metastasis at presentation. BRAFV600E or RAS mutations (27% and 24% of cases, respectively) remain mutually exclusive main drivers in PDTC. TERT promoter mutations represent the most common alteration in PDTC (40%). Mutation in translation initiation factor EIF1AX (11%) and tumor suppressor TP53 (16%) have also been reported in PDTC. High rates of novel mutations (MED12 and RBM10) have been reported in fatal PDTC (15% and 12%, respectively). Chromosome 1q gains represent the most common arm-level alterations in PDTC, and those patients show worse survival rates. Chromosome 22q losses are also found in PDTC and show strong association with RAS mutation.
CONCLUSIONS: These new insights into the clinicopathologic and molecular characteristics of PDTC, together with further advancement in ultra-deep sequencing technologies, will be conducive in narrowing the focus in order to develop novel targeted therapies and improve the outcomes in PDTC patients.

PMID 30747050
Iñigo Landa, Tihana Ibrahimpasic, Laura Boucai, Rileen Sinha, Jeffrey A Knauf, Ronak H Shah, Snjezana Dogan, Julio C Ricarte-Filho, Gnana P Krishnamoorthy, Bin Xu, Nikolaus Schultz, Michael F Berger, Chris Sander, Barry S Taylor, Ronald Ghossein, Ian Ganly, James A Fagin
Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers.
J Clin Invest. 2016 Mar 1;126(3):1052-66. doi: 10.1172/JCI85271. Epub 2016 Feb 15.
Abstract/Text BACKGROUND: Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization.
METHODS: We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC).
RESULTS: Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation.
CONCLUSIONS: These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality.
FUNDING: This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.

PMID 26878173
Iwao Sugitani, Akira Miyauchi, Kiminori Sugino, Takahiro Okamoto, Akira Yoshida, Shinichi Suzuki
Prognostic factors and treatment outcomes for anaplastic thyroid carcinoma: ATC Research Consortium of Japan cohort study of 677 patients.
World J Surg. 2012 Jun;36(6):1247-54. doi: 10.1007/s00268-012-1437-z.
Abstract/Text BACKGROUND: Anaplastic thyroid carcinoma (ATC) accounts for only 1 to 2% of all thyroid carcinomas, but it is one of the most lethal neoplasms in humans. To date, most findings about ATC have been derived from single-institution studies with limited numbers of cohorts. To obtain further insights into this "orphan disease," we have established a multicenter registry, the ATC Research Consortium of Japan (ATCCJ). We analyzed prognostic factors and treatment outcomes using the large cohort database of the ATCCJ.
METHODS: Most of the Japanese centers involved in the treatment of thyroid cancer were invited to join the ATCCJ and have provided information on ATC patients treated between 1995 and 2008. The database includes 677 cases from 38 registered institutions. Survival curves were determined using Kaplan-Meier methods and were compared using the log-rank test. Cox's proportional hazards model was used for multivariate analysis.
RESULTS: Clinical varieties of ATC were classified into four types: common type (n = 547); incidental type (n = 29); anaplastic transformation at the neck (n = 95); anaplastic transformation at a distant site (n = 6). The incidental type followed by anaplastic transformation at the neck showed better outcomes than the other types. Anaplastic transformation at a distant site showed the worst outcomes. The 6-month and 1-year cause-specific survival (CSS) rates for common-type ATC were 36 and 18%, respectively. In all, 84 (15%) achieved long-term (>1 year) survival. Multivariate analysis identified age ≥70 years, presence of acute symptoms, leukocytosis (white blood cell count ≥10,000/mm(3)), large tumor >5 cm, T4b tumor, and distant metastasis as significant risk factors for lower survival. CSS rates also differed significantly depending on UICC stages, with 6-month CSSs of 60% for stage IVA, 45% for IVB, and 19% for IVC. For 36 of 69 (52%) stage IVA patients who underwent radical surgery, adjuvant therapies, including radiation therapy (RTX) and chemotherapy (CTX) did not show additional benefit statistically. Conversely, among 242 stage IVB patients, 80 (33%) underwent radical surgery. For those patients, therapies combining RTX with CTX significantly improved CSS.
CONCLUSIONS: Long-term survival is possible for selected patients with ATC. To determine the treatment strategy, UICC stage (disease extent) and other prognostic factors (e.g., biologic malignancy grade) should be considered.

PMID 22311136
Naoyoshi Onoda, Iwao Sugitani, Ken-Ichi Ito, Akifumi Suzuki, Takuya Higashiyama, Tatsuya Fukumori, Nobuyasu Suganuma, Katsuhiko Masudo, Hirotaka Nakayama, Atsuhiko Uno, Katsunari Yane, Seiichi Yoshimoto, Aya Ebina, Yukari Kawasaki, Shigeto Maeda, Manabu Iwadate, Shinichi Suzuki
Evaluation of the 8th Edition TNM Classification for Anaplastic Thyroid Carcinoma.
Cancers (Basel). 2020 Feb 27;12(3). doi: 10.3390/cancers12030552. Epub 2020 Feb 27.
Abstract/Text BACKGROUND: The tumor-node-metastasis (TNM) classification system to categorized anaplastic thyroid cancer (ATC) was revised.
METHODS: The revised system was evaluated using a large database of ATC patients.
RESULTS: A total of 757 patients were analyzed. The proportion and median overall survival values (OS: months) for each T category were T1 (n = 8, 1.1%, 12.5), T2 (n = 43, 5.7%, 10.9), T3a (n = 117, 15.5%, 5.7), T3b (n = 438, 57.9%, 3.9), and T4 (n = 151, 19.9%, 5.0). The OS of the N0 and N1 patients were 5.9 and 4.3, respectively (log-rank p < 0.01). Sixty-three (58.3%) patients migrated from stage IV A to IV B by revision based on the existence of nodal involvement and 422 patients (55.7%) were stratified into stage IV B, without a worsening of their OS (6.1), leaving 45 patients (5.9%) in stage IV A with fair OS (15.8). The hazard ratios for the survival of the patients of stage IV B compared to stage IV A increased from 1.1 to 2.1 by the revision. No change was made for stage IV C (n = 290, 38.8%, 2.8).
CONCLUSION: The revised TNM system clearly indicated the prognoses of ATC patients by extracting rare patients with fair prognoses as having stage IV A disease and categorized many heterogeneous patients in stage IV B.

PMID 32120853
I Sugitani, N Kasai, Y Fujimoto, A Yanagisawa
Prognostic factors and therapeutic strategy for anaplastic carcinoma of the thyroid.
World J Surg. 2001 May;25(5):617-22. doi: 10.1007/s002680020166.
Abstract/Text Although anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, a few patients survive for a fairly long time after modern intensive treatment. We tried to identify prognostic factors of ATC to assist in deciding on the proper therapeutic strategy in individual patients. Of 47 patients with ATC (1976-1999), 3 patients with "incidental" ATC (largely differentiated thyroid carcinoma with a small region of ATC) were excluded because they had a favorable outcome. The 1-year survival rate of the remaining 44 patients with clinically distinct ATC was 16%. The presence of acute symptoms, large tumor (> 5 cm), distant metastasis, and leukocytosis (white blood cell count > or = 10,000/mm3) proved to be significant risk factors. Multivariate analysis by the Cox proportional hazard model showed that these four factors were independent factors for predicting death from ATC. We devised a novel prognostic index (PI) based on the number of these four unfavorable characteristics the patient possessed. Patients with a PI of < or =1 had a 62% survival rate at 6 months, whereas no patients with a PI of > or =3 survived longer than 6 months. All patients with a PI of 4 died from their disease within 3 months. Nine patients received multimodal treatment with a combination of surgery, external irradiation, and chemotherapy and had a long survival (mean 333 +/- 68 days; one patient is still alive and tumor-free), with a mean PI of 0.6. Our PI is useful as a means of selecting patients for aggressive therapy. When the PI is low, multimodal treatment should be attempted to obtain the best survival results; if it is high most patients are too seriously ill to tolerate intensive treatment and palliative therapy is recommended.

PMID 11369989
Andreas Machens, Henning Dralle
Biomarker-based risk stratification for previously untreated medullary thyroid cancer.
J Clin Endocrinol Metab. 2010 Jun;95(6):2655-63. doi: 10.1210/jc.2009-2368. Epub 2010 Mar 25.
Abstract/Text CONTEXT: Preoperative neck ultrasonography may yield false-negative findings in more than one-third of medullary thyroid cancer (MTC) patients. If not cleared promptly, cervical lymph node metastases may emerge subsequently. Reoperations entail an excess risk of surgical morbidity and may be avoidable.
OBJECTIVE: This comprehensive investigation aimed to evaluate in a head-to-head comparison the clinical utility of pretherapeutic biomarker serum levels (basal calcitonin; stimulated calcitonin; carcinoembryonic antigen) for indicating extent of disease and providing biochemical stratification of pretherapeutic MTC risk.
DESIGN: This was a retrospective analysis.
SETTING: The setting was a tertiary referral center.
PATIENTS: Included were 300 consecutive patients with previously untreated MTC.
INTERVENTIONS: The intervention was compartment-oriented surgery.
MAIN OUTCOME MEASURE: Stratified biomarker levels were correlated with histopathologic extent of disease.
RESULTS: Higher biomarker levels reflected larger primary tumors and more lymph node metastases. Stratified basal calcitonin serum levels correlated better (r = 0.59) with the number of lymph node metastases than carcinoembryonic antigen (r = 0.47) or pentagastrin-stimulated calcitonin (r = 0.40) levels. Lymph node metastases were present in the ipsilateral central and lateral neck, contralateral central neck, contralateral lateral neck, and upper mediastinum, respectively, beyond basal calcitonin thresholds of 20, 50, 200, and 500 pg/ml. Bilateral compartment-oriented neck surgery achieved biochemical cure in at least half the patients with pretherapeutic basal calcitonin levels of 1,000 pg/ml or less but not in patients with levels greater than 10,000 pg/ml.
CONCLUSIONS: Most newly diagnosed MTC patients, i.e. those with pretherapeutic basal calcitonin levels greater than 200 pg/ml, may need bilateral compartment-oriented neck surgery to reduce the number of reoperations.

PMID 20339026
Francesca Torresan, Elisabetta Cavedon, Caterina Mian, Maurizio Iacobone
Long-Term Outcome After Surgery for Medullary Thyroid Carcinoma: A Single-Center Experience.
World J Surg. 2018 Feb;42(2):367-375. doi: 10.1007/s00268-017-4321-z.
Abstract/Text BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare C cells-derived tumor, with a hardly predictable long-term prognosis. This study was aimed to evaluate the predictive factors of cure and survival after surgery for MTC in a monocentric series.
METHODS: A retrospective analysis of the long-term outcomes was assessed in 255 MTC patients operated between 1980 and 2015 at Padua University hospital.
RESULTS: Sporadic MTC occurred in 65.1% and hereditary MTC in 34.9% of patients. At a median follow-up of 93 months (range 7-430), the cure rate was 56.8%. The overall 10-year survival was 84.4%, and MTC-related death rate was 15.3%. Patients who died because of MTC had a median age of 61 years (range 21-84) and were at stages III-IV in all cases; deaths occurred in 18% of sporadic MTC, 6% of MEN2a and 66.7% of MEN2b patients. None of the patients at stages I-II died because of the disease, but 17.7% had persistent/recurrent disease. Based on univariate analysis, age, gender, genetic variant, extent and year of surgery, tumor size, lymph-nodal metastases and tumor stage significantly affected cure and survival rates. At multivariate analysis, only patient- and tumor-related features (age, lymph-nodal status and stage) remained significant independent prognostic factors.
CONCLUSIONS: Radical surgery is the only chance of definitive cure in MTC, but it is possible only at early stage; in advanced stages, even extensive surgery could not grant cure and prolonged survival. Stage, nodal metastases and age remain the main predictive factors for cure and survival.

PMID 29134313
Yasuhiro Ito, Akira Miyauchi, Minoru Kihara, Takuya Higashiiyama, Mitsuhiro Fukushima, Akihiro Miya
Static Prognostic Factors and Appropriate Surgical Designs for Patients with Medullary Thyroid Carcinoma: The Second Report from a Single-Institution Study in Japan.
World J Surg. 2018 Dec;42(12):3954-3966. doi: 10.1007/s00268-018-4738-z.
Abstract/Text BACKGROUND: Medullary thyroid carcinoma (MTC) originates from calcitonin-producing cells of the thyroid. In 2009, we published our first report on the biological characteristics and prognosis of 118 MTC patients. Herein, we enrolled a larger number of patients with longer follow-up periods to further study the biological characteristics and appropriate therapies for MTC.
METHODS: In general, hemithyroidectomy and total thyroidectomy were performed for sporadic MTC confined to the thyroid lobe and for hereditary MTC with central node dissection, respectively. Moreover, prophylactic modified radical neck dissection was performed on the side of macroscopic tumors.
RESULTS: In total, 233 patients (99 hereditary and 134 sporadic) were enrolled. The median follow-up time was 128 months (range 7-445 months). Biochemical cure was obtained in 36 (62%) of the 58 patients who underwent prophylactic MND and were pathologically positive for lateral node metastasis. None of the patients had recurrence in the preserved thyroid. Distant recurrence was detected in 19 patients, and 12 died of MTC. Preoperative calcitonin and carcinoembryonic antigen levels, tumor size (T) > 4 cm, the male sex, clinical and pathological node metastases (N1), distant metastasis (M1), extrathyroid extension (Ex), and a lack of biochemical cure had prognostic impacts on distant recurrence and/or carcinoma-related mortality on univariate analysis. On multivariate analysis, Ex was independently correlated with distant recurrence, and Ex, T > 4 cm, and M1 independently affected carcinoma-related mortality.
CONCLUSION: MTC patients had excellent prognosis in our institutions, indicating that our surgical strategies were appropriate.

PMID 30051240
Sunghwan Suh, Yun Hak Kim, Tae Sik Goh, Jin Lee, Dae Cheon Jeong, Sae-Ock Oh, Jong Chul Hong, Seong Jang Kim, In Joo Kim, Kyoungjune Pak
Outcome prediction with the revised American joint committee on cancer staging system and American thyroid association guidelines for thyroid cancer.
Endocrine. 2017 Dec;58(3):495-502. doi: 10.1007/s12020-017-1449-4. Epub 2017 Oct 13.
Abstract/Text BACKGROUND: Several staging systems have been developed to predict the risk of mortality in patients with differentiated thyroid cancer (DTC). However, none of them have been shown to be clearly superior to the other.
METHODS: We compared the patient outcome predictability of recently revised staging systems predictability of patient outcome using data from The Cancer Genome Atlas. To set a comparison among American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging 7th, 8th editions, American Thyroid Association guidelines 2009 and 2015, concordance index (c-index), Akaike information criterion (AIC), Bayesian information criterion (BIC), and Brier score were applied to quantify the predictive ability of a survival model, to select the statistical model, and to measure the accuracy of probabilistic predictions.
RESULTS: A total of 457 patients with papillary thyroid cancer having a mean age of 45.9 years were included in this study (120 males, 337 females). Among these patients, 43 (9.4%) experienced recurrence/progression during the follow-up (591.2 ± 833.5 months). Among the models used, the AJCC/UICC 8th edition, which showed the highest c-index and lowest AIC, BIC, and Brier score, was identified as the best among the models used.
CONCLUSION: AJCC/UICC 8th edition predicted patient outcome more accurately than the other staging systems.

PMID 29030773
Yasuhiro Ito, Akira Miyauchi, Mitsuyoshi Hirokawa, Masatoshi Yamamoto, Hitomi Oda, Hiroo Masuoka, Hisanori Sasai, Mitsuhiro Fukushima, Takuya Higashiyama, Minoru Kihara, Akihiro Miya
Prognostic value of the 8th edition of the tumor-node-metastasis classification for patients with papillary thyroid carcinoma: a single-institution study at a high-volume center in Japan.
Endocr J. 2018 Jul 28;65(7):707-716. doi: 10.1507/endocrj.EJ18-0019. Epub 2018 Apr 20.
Abstract/Text The tumor-node-metastasis (TNM) staging system is most commonly adopted to evaluate the prognosis of patients with thyroid carcinoma. The 8th edition of the TNM staging system, an extensively revised version of the 7th edition, was recently released. We aimed to investigate whether and how well the 8th edition reflects the cause-specific survival (CSS) of patients with papillary thyroid carcinoma by analyzing the cases in 5,892 patients who underwent initial surgery at Kuma Hospital between 1987 and 2005. The median postoperative follow-up duration was 178 months (range: 6-357 months). One patient with T4b disease was excluded from the analysis. Overall, 116 (2.0%) patients died of thyroid carcinoma. The proportion of variance explained (PVE) for CSS in the 7th and 8th editions was 10.69 and 10.97, respectively. Using the 7th edition, CSS of patients with stage IVA and stage III disease was similar (p = 0.32). In contrast, using the 8th edition, CSS was poorer in stage II than in stage I (p < 0.001), in stage III than in stage II (p < 0.001), and in stage IVB than in stage III (p < 0.001). Similar results were observed for disease-free survival. Although we could not establish any objective evidence that the 8th edition is superior to the 7th edition, the 8th edition is simpler and more convenient, as it includes fewer stages and addresses the issue of the 7th edition where stage IVA and III patients had similar prognoses.

PMID 29681581
Lauren N Pontius, Taofik O Oyekunle, Samantha M Thomas, Michael T Stang, Randall P Scheri, Sanziana A Roman, Julie A Sosa
Projecting Survival in Papillary Thyroid Cancer: A Comparison of the Seventh and Eighth Editions of the American Joint Commission on Cancer/Union for International Cancer Control Staging Systems in Two Contemporary National Patient Cohorts.
Thyroid. 2017 Nov;27(11):1408-1416. doi: 10.1089/thy.2017.0306. Epub 2017 Oct 5.
Abstract/Text BACKGROUND: This study aims to compare the seventh and eighth editions of the American Joint Commission on Cancer/Union for International Cancer Control (AJCC/UICC) tumor, node, metastasis staging system for patients with papillary thyroid cancer (PTC) in two national patient cohorts.
METHODS: Adult PTC patients undergoing surgery were selected from the Surveillance, Epidemiology and End Results (SEER) program (2004-2012) and the National Cancer Database (2004-2012). Staging criteria for the seventh and eighth AJCC/UICC editions were applied separately to each cohort. Survival probabilities were estimated using the Kaplan-Meier method. Multivariable Cox proportional hazards models were used to estimate the association of stage with survival in both settings. The Akaike information criterion was used to assess model performance.
RESULTS: About 23% of patients were downstaged from the seventh to the eighth edition in SEER, while 24% were downstaged in the National Cancer Database. Disease-specific survival (DSS) and overall survival (OS) were significantly related to stage at diagnosis when using both the seventh and eighth editions of the AJCC/UICC staging system (p < 0.001). Patients classified into higher stages (III and IV) in the eighth edition showed a worse prognosis than those classified into similar stages in the seventh edition. After adjustment, PTC stages as defined by both editions were significantly associated with DSS and OS. With respect to both DSS and OS, the eighth edition PTC model appeared to be a better fit to the data (smaller Akaike information criterion values) compared to the seventh edition.
CONCLUSION: Based on these large contemporary national cohorts, the eighth edition AJCC/UICC tumor, node, metastasis classification for PTC is superior to the seventh edition for predicting survival.

PMID 28891405
R Michael Tuttle, Bryan Haugen, Nancy D Perrier
Updated American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System for Differentiated and Anaplastic Thyroid Cancer (Eighth Edition): What Changed and Why?
Thyroid. 2017 Jun;27(6):751-756. doi: 10.1089/thy.2017.0102. Epub 2017 May 19.
Abstract/Text
PMID 28463585
Elisa Pasqual, Julie Ann Sosa, Yingxi Chen, Sara J Schonfeld, Amy Berrington de González, Cari M Kitahara
Trends in the Management of Localized Papillary Thyroid Carcinoma in the United States (2000-2018).
Thyroid. 2022 Apr;32(4):397-410. doi: 10.1089/thy.2021.0557. Epub 2022 Mar 15.
Abstract/Text Background: In response to evidence of overdiagnosis and overtreatment of papillary thyroid carcinoma (PTC), the 2009 and 2015 American Thyroid Association (ATA) adult guidelines recommended less extensive surgery (lobectomy vs. total thyroidectomy) and more restricted use of postsurgical radioactive iodine (RAI) in management of PTC at low risk of recurrence. In 2015, active surveillance was suggested as a viable option for some <1-cm PTCs, or microcarcinomas. The 2015 ATA pediatric guidelines similarly shifted toward more restricted use of RAI for low-risk PTCs. The impact of these recommendations on low-risk adult and pediatric PTC management remains unclear, particularly after 2015. Methods: Using data from 18 Surveillance, Epidemiology, and End Results (SEER) U.S. registries (2000-2018), we described time trends in reported first-course treatment (total thyroidectomy alone, total thyroidectomy+RAI, lobectomy, no surgery, and other/unknown) for 105,483 patients diagnosed with first primary localized PTC (without nodal/distant metastases), overall and by demographic and tumor characteristics. Results: The declining use of RAI represented the most pronounced change in management of PTCs <4 cm (44-18% during the period 2006-2018), including microcarcinomas (26-6% during the period 2007-2018). In parallel, an increasing proportion of PTCs were managed with total thyroidectomy alone (35-54% during the period 2000-2018), while more subtle changes were observed for lobectomy (declining from 23% to 17% during the period 2000-2006, stabilizing, and then rising from 17% to 24% during the period 2015-2018). Use of nonsurgical management did not meaningfully change over time, impacting <1% of microcarcinomas annually during the period 2000-2018. Similar treatment trends were observed by sex, age, race/ethnicity, metropolitan vs. nonmetropolitan residence, and insurance status. For pediatric patients (<20 years), use of RAI peaked in 2009 (59%), then decreased markedly to 11% (2018), while use of total thyroidectomy alone and, to a lesser extent, lobectomy increased. No changing treatment trends were observed for ≥4-cm PTCs. Conclusions: The declining use of RAI in management of low-risk adult and pediatric PTC is consistent with changing recommendations from the ATA practice guidelines. Post-2015 trends in use of lobectomy and nonsurgical management of low-risk PTCs, particularly microcarcinomas, were more subtle than expected; however, these trends may change as evidence regarding their safety continues to emerge.

PMID 35078347
Yasuhiro Ito, Takumi Kudo, Minoru Kihara, Yuuki Takamura, Kaoru Kobayashi, Akihiro Miya, Akira Miyauchi
Prognosis of low-risk papillary thyroid carcinoma patients: its relationship with the size of primary tumors.
Endocr J. 2012;59(2):119-25. doi: 10.1507/endocrj.ej11-0288. Epub 2011 Nov 9.
Abstract/Text It is well-known that papillary thyroid carcinoma (PTC) has a generally indolent character and shows a favorable prognosis unless it has no high-risk features such as clinical lymph node metastasis, distant metastasis, and significant extrathyroid extension. In this study, we investigated the prognosis of 3,965 patients with PTC without these features. We classified these patients into 3 groups: T-1, tumor ≤ 2 cm (n = 2,591); T-2, tumor 2.1-4 cm (n = 1,123); T-3, tumor > 4 cm (n = 251). Ten-year recurrence rates of T-1, T-2, and T-3 patients were 0.3, 1.3, and 1.9% for the thyroid (in the subset of patients who underwent limited thyroidectomy), 1.9, 4.6, and 8.1% for lymph nodes, and 0.4, 1.6, and 3.4% for distant organs, respectively. A tumor size larger than 2 cm had an independent prognostic impact on all these recurrences also on multivariate analysis. These findings suggest that PTC larger than 2 cm exhibited more aggressive biological characteristics than that measuring 2 cm or less, even though it had no other high-risk features. However, the incidences of distant recurrence and carcinoma death were still low and it remains unclear whether extensive surgery is mandatory for otherwise low-risk PTC patients with large tumor.

PMID 22068114
Kenichi Matsuzu, Kiminori Sugino, Katsuhiko Masudo, Mitsuji Nagahama, Wataru Kitagawa, Hiroshi Shibuya, Keiko Ohkuwa, Takashi Uruno, Akifumi Suzuki, Syunsuke Magoshi, Junko Akaishi, Chie Masaki, Michikazu Kawano, Nobuyasu Suganuma, Yasushi Rino, Munetaka Masuda, Kaori Kameyama, Hiroshi Takami, Koichi Ito
Thyroid lobectomy for papillary thyroid cancer: long-term follow-up study of 1,088 cases.
World J Surg. 2014 Jan;38(1):68-79. doi: 10.1007/s00268-013-2224-1.
Abstract/Text BACKGROUND: Total thyroidectomy is well accepted as initial surgery for papillary thyroid cancer (PTC), but the extent of the thyroidectomy remains a matter of controversy. This study was designed to investigate the long-term clinical outcome of PTC patients who had undergone thyroid lobectomy and to elucidate the indications of lobectomy as initial surgery.
METHODS: The cases of 1,088 PTC patients who underwent thyroid lobectomy with curative intent at Ito Hospital between 1986 and 1995 were analyzed retrospectively in this study. None of the patients had received postoperative radioactive iodine (RAI) ablation therapy. The median follow-up period was 17.6 years. All clinical outcomes, including recurrence and death as a result of PTC or other reasons, were evaluated. To establish the indications for lobectomy as initial surgery for PTC, the potential risk factors, such as age, sex, primary tumor size, extrathyroidal invasion, and clinical lymph node metastasis at the time of the initial surgery, were assessed statistically for associations with recurrence and disease-related death.
RESULTS: The remnant-thyroid recurrence-free survival (RT-RFS) rate, the regional- lymph-node recurrence-free survival (L-RFS) rate, and the distant-recurrence-free survival (D-RFS) rate as of 25 years after surgery were 93.5, 90.6, and 93.6%, respectively. The cause-specific survival (CSS) rate at 25 years was 95.2%. Univariate and multivariate analyses showed that none of the factors assessed were significantly associated with the RT-RFS rate. Tumor size, clinical lymph node metastasis, and extrathyroidal invasion were significantly associated with the L-RFS rate. The D-RFS and CSS rates were both significantly lower in the group of patients who were aged 45 years old or older, the group whose tumors were larger than 40 mm, and the group with extrathyroidal invasion. Based on the above findings, we classified the patients into four groups according to age <45 or ≥ 45 years, tumor size ≤ 40 or >40 mm, whether clinical lymph node metastasis was present, and whether extrathyroidal invasion was present. None of the patients without any of these four risk factors died of PTC. On the other hand, 22 patients who died of PTC were positive for one or more of these four factors.
CONCLUSIONS: The long-term clinical outcome of the PTC patients who had been treated by lobectomy without RAI ablation was excellent. Based on the above results, we concluded that lobectomy is a valid alternative to total thyroidectomy for the treatment of PTC patients who are younger than aged 45 years, whose tumor diameter is 40 mm or less, and who do not have clinical lymph node metastasis or extrathyroidal invasion.

PMID 24081532
Arin L Madenci, Diana Caragacianu, Jacob O Boeckmann, Brendan C Stack, Jennifer J Shin
Lateral neck dissection for well-differentiated thyroid carcinoma: a systematic review.
Laryngoscope. 2014 Jul;124(7):1724-34. doi: 10.1002/lary.24583. Epub 2014 Feb 10.
Abstract/Text OBJECTIVES/HYPOTHESIS: Management of the lateral neck in well-differentiated thyroid carcinoma (WDTC) remains a topic of ongoing debate. A systematic review was performed to determine if patients with WDTC who undergo lateral neck dissection (LND) have significantly different survival, recurrence, or procedure-related complication rates, as compared to those who do not.
DATA SOURCES: A computerized search of MEDLINE from 1966 to October 2012 was performed, supplemented with manual searches.
REVIEW METHODS: A priori criteria were used to evaluate 924 studies. Data extraction was performed by independent reviewers and focused on survival, recurrence, postoperative complications, study designs, and potential confounders.
RESULTS: Forty-seven criterion-meeting studies included 24,153 participants. Stage-specific data were limited. The small volume of data specific to the N0 neck (n=3 studies, 6.3%) demonstrates no difference in disease-free survival (DFS) or recurrence with versus without LND. The data regarding the N+ neck (n=14 studies, 29.2%) were mixed with regard to the impact of LND on DFS and recurrence. The preponderance of data was reported in analyses of mixed or unreported nodal status (n=31 studies, 64.6%). Among these studies, the majority reported no difference in overall survival, DFS, disease-specific survival, or recurrence, but overall data were mixed and subject to confounding by indication and limitations in power.
CONCLUSIONS: Data regarding the impact of LND on survival, recurrence, and postoperative complications are mixed. Routine prophylactic LND for WDTC does not have a clearly advantageous risk-to-benefit ratio.

© 2014 The American Laryngological, Rhinological and Otological Society, Inc.
PMID 24390830
Yasuhiro Ito, Mitsuyoshi Hirokawa, Hiroo Masuoka, Takuya Higashiyama, Minoru Kihara, Naoyoshi Onoda, Akihiro Miya, Akira Miyauchi
Prognostic factors for follicular thyroid carcinoma: the importance of vascular invasion.
Endocr J. 2022 Apr 29;. doi: 10.1507/endocrj.EJ22-0077. Epub 2022 Apr 29.
Abstract/Text The World Health Organization (WHO) classifies follicular thyroid carcinoma (FTC) into three categories: minimally invasive (mFTC), encapsulated angioinvasive (eaFTC), and widely invasive (wFTC). This study investigated whether this classification is appropriate. We enrolled 523 patients who underwent initial surgery at Kuma Hospital between 1998 and 2015 and were diagnosed with FTC. Capsular invasion (CI) was classified as none, minimal (microscopic), or wide (macroscopic) invasion. Vascular invasion (VI) was divided according to the number of invasive foci into three degrees: VI(-), VI(1+), and VI(2+). For 507 M0 patients, age ≥55 years (p = 0.004), non-oxyphilic histology (p = 0.043), and male sex (p < 0.001) predicted poor distant recurrence-free survival (DR-FS) on univariate analysis; however, tumor size >4 cm and wide CI did not. The DR-FS rates significantly decreased from VI(-) to VI(2+) in a step-by-step fashion, including VI(-) vs. VI(1+) (p = 0.011) and VI(1+) vs. VI(2+) (p = 0.014). Multivariate analysis revealed that older age (p = 0.0004), non-oxyphilic histology (p = 0.041), male sex (p = 0.0052), VI(1+) (p = 0.017), and VI(2+) (p < 0.001) independently predicted distant recurrence. The DR-FS rates did not significantly differ among mFTC, wFTC/VI(-), and eaFTC/VI(1+). The DR-FS rate of eaFTC/VI(2+) was worse than that of eaFTC/VI(1+) (p = 0.042), but did not differ from that of wFTC/VI(1+/2+). Our findings suggest that subclassifying eaFTC according to the degree of VI and restricting wFTC to VI-positive cases would be better in the WHO classification. Revising the definition for wide CI is recommended.

PMID 35491160
Kelly F Moyer, Andrea R Marcadis, Ashok R Shaha
Airway management, symptom relief and best supportive care in anaplastic thyroid cancer.
Curr Opin Otolaryngol Head Neck Surg. 2020 Apr;28(2):74-78. doi: 10.1097/MOO.0000000000000619.
Abstract/Text PURPOSE OF REVIEW: Anaplastic thyroid cancer (ATC) is a rare but aggressive form of thyroid cancer that is associated with significant morbidity and mortality. Because ATC is locally invasive, airway management is a critical component of treating these patients. Timely decisions regarding airway interventions can contribute to symptom relief and supportive care for patients. Over the last decade, there has been a paradigm shift in our recommendations for airway management. The purpose of this review is to summarize airway management, symptom relief and best supportive care for patients with ATC.
RECENT FINDINGS: More recent literature discusses the morbidities associated with tracheostomy and instead focuses on the benefits of supportive care and surgical resection. The multidisciplinary treating team should initiate early discussions for airway management, end-of-life care and palliative goals for patients with ATC. Tracheostomy should be offered to patients with careful thought and preoperative planning.
SUMMARY: Our goal in symptom relief and airway management is to improve the quality of life of patients with ATC and avoid the unnecessary morbidity of tracheostomy until clinically indicated.

PMID 32022733
Megan R Haymart, Mousumi Banerjee, Huiying Yin, Francis Worden, Jennifer J Griggs
Marginal treatment benefit in anaplastic thyroid cancer.
Cancer. 2013 Sep 1;119(17):3133-9. doi: 10.1002/cncr.28187. Epub 2013 Jul 9.
Abstract/Text BACKGROUND: Because anaplastic thyroid cancer is a rare malignancy with a high mortality rate, the benefit of multimodality treatment was evaluated.
METHODS: Overall survival was determined in the 2742 patients captured by the National Cancer Database who were diagnosed with anaplastic thyroid cancer between 1998 and 2008. Kaplan-Meier analysis and then Cox proportional hazard regression was performed, controlling for patient characteristics and treatment.
RESULTS: Only older age (adjusted hazard ratio [AHR] for  ≥  85 years = 3.43, 95% confidence interval [CI] = 2.34-5.03; for 75-84 years, AHR = 2.85, 95% CI = 1.97-4.11; for 65-74 years, AHR = 2.20, 95% CI = 1.53-3.15; for 45-64 years, AHR = 2.08, 95% CI = 1.47-2.95) and omission of treatment were associated with greater mortality (omission of surgery: AHR = 1.79, 95% CI = 1.61-1.99; omission of radiation therapy: AHR = 1.56; 95% CI = 1.41-1.73; and omission of chemotherapy: AHR = 1.28, 95% CI = 1.15-1.43). In subgroup analysis of patients with American Joint Committee on Cancer stage IVA, IVB, and IVC anaplastic thyroid cancer, combination therapy with surgery, radiation, and chemotherapy was associated a difference in median survival of months.
CONCLUSIONS: Multimodality management of anaplastic thyroid cancer results in a marginal treatment benefit. The poor overall survival of all anaplastic thyroid cancer patients, regardless of treatment, emphasizes the need for informed patients whose preferences are incorporated into treatment decision-making.

Copyright © 2013 American Cancer Society.
PMID 23839797
Naoyoshi Onoda, Kiminori Sugino, Takuya Higashiyama, Makoto Kammori, Kazuhisa Toda, Ken-Ichi Ito, Akira Yoshida, Nobuyasu Suganuma, Noriaki Nakashima, Shinichi Suzuki, Kiyoaki Tsukahara, Hitoshi Noguchi, Masanori Koizumi, Toshimitsu Nemoto, Hisato Hara, Akira Miyauchi, Iwao Sugitani
The Safety and Efficacy of Weekly Paclitaxel Administration for Anaplastic Thyroid Cancer Patients: A Nationwide Prospective Study.
Thyroid. 2016 Sep;26(9):1293-9. doi: 10.1089/thy.2016.0072.
Abstract/Text BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare and extremely aggressive malignancy, with a median survival of less than 6 months due to rapid progression and resistance to multimodal therapies. Effective treatment strategies have not been identified. A prospective clinical study was performed to objectively evaluate outcomes of treatment with paclitaxel.
METHODS: An investigator-initiated, multicenter, nonrandomized, open-label, single-arm study to evaluate the feasibility and efficacy of weekly paclitaxel (80 mg/m(2)) administration for patients with pathologically confirmed ATC was conducted in a nationwide organization.
RESULTS: Feasibility was analyzed in 56 patients. More than one course of treatment was performed in 52 (93%) patients retaining sufficient dose intensity (>84%). No patient had to terminate the treatment because of an adverse event. The median overall survival was 6.7 months [confidence interval 4.4-9.0]. The 6-month survival was 54%. Among the 42 patients with an evaluable lesion, none demonstrated complete remission, 9 (21%) showed partial remission, 22 (52%) achieved stable disease, and 8 (19%) exhibited progressive disease; 3 did not complete the initial treatment course. The objective response rate was 21%, and the clinical benefit rate was 73%. The median time to progression was 1.6 months. Statistically, no additional effect of concomitant radiation was demonstrated in 6 patients receiving combined therapy. Eight patients, in whom a complete post-treatment surgical removal of the tumor was feasible, survived significantly longer (median 7.6 months [CI 8.1-23.0]) than the other 34 patients in whom the tumor could not be completely removed after chemotherapy (5.4 months [CI 3.0-7.8], p = 0.018).
SUMMARY: The study demonstrates objective and accurate information concerning the feasibility and efficacy of a standardized treatment with weekly paclitaxel administration for ATC patients.
CONCLUSIONS: Weekly paclitaxel administration for ATC patients can be of clinical benefit in a neo-adjuvant setting.

PMID 27484330
Takuya Higashiyama, Yasuhiro Ito, Mitsuyoshi Hirokawa, Mitsuhiro Fukushima, Takashi Uruno, Akihiro Miya, Fumio Matsuzuka, Akira Miyauchi
Induction chemotherapy with weekly paclitaxel administration for anaplastic thyroid carcinoma.
Thyroid. 2010 Jan;20(1):7-14. doi: 10.1089/thy.2009.0115.
Abstract/Text BACKGROUND: Anaplastic thyroid carcinoma (ATC) has a very dire prognosis and no effective therapeutic strategies have been established for ATC patients, especially those with stage IVB or IVC. Our objective was to investigate the effectiveness of weekly paclitaxel administered as induction chemotherapy and to establish novel therapeutic strategies for ATC.
METHODS: We performed induction chemotherapy by weekly paclitaxel administration for patients with stage IVB (nine patients) and IVC (four patients) disease. Clinical and histological responses were assessed. Overall survival was compared with that of ATC patients with stage IVB (n = 50) and IVC (n = 13) treated without paclitaxel.
RESULTS: One patient demonstrated complete response (CR) and two demonstrated partial response (PR) in the stage IVB group (response rate: 33%), and one patient showed PR in stage IVC (response rate: 25%). Curative surgery and adjuvant therapy were performed for four patients with stage IVB, and 32 months after treatment, all the four are alive and free of disease. One CR patient and one stable disease patient were assessed as grade IV (complete remission) and grade III (nearly CR) on histological response, respectively. All four patients with stage IVC died of carcinoma within 8 months. Overall survival of stage IVB patients with induction chemotherapy was better (p = 0.0213) than that without the chemotherapy and also better (p = 0.0467) than those with chemotherapy other than paclitaxel. However, induction chemotherapy did not improve the overall survival of stage IVC patients (p = 0.2002).
CONCLUSIONS: Induction chemotherapy by weekly paclitaxel is a promising therapeutic strategy for stage IVB ATC patients. Responders can be expected to achieve long-term survival. We could not get significant difference of overall survival between stage IVC patients with or without weekly induction paclitaxel, although there were some cases that responded well.

PMID 20025538
Takuya Higashiyama, Kiminori Sugino, Hisato Hara, Ken-Ichi Ito, Noriaki Nakashima, Naoyoshi Onoda, Masayuki Tori, Hiroshi Katoh, Naomi Kiyota, Ichiro Ota, Nobuyasu Suganuma, Yatsuka Hibi, Toshimitsu Nemoto, Shunji Takahashi, Katsunari Yane, Tetsuya Ioji, Shinsuke Kojima, Hideaki Kaneda, Iwao Sugitani, Makoto Tahara
Phase II study of the efficacy and safety of lenvatinib for anaplastic thyroid cancer (HOPE).
Eur J Cancer. 2022 Aug 3;173:210-218. doi: 10.1016/j.ejca.2022.06.044. Epub 2022 Aug 3.
Abstract/Text PURPOSE: Anaplastic thyroid cancer (ATC) is a rare and highly aggressive cancer for which effective systemic therapy has long been sought. Here, we assessed the efficacy and safety of lenvatinib in patients with unresectable ATC.
PATIENTS AND METHODS: The study was investigator-initiated and conducted under a multicenter, open-label, nonrandomized, phase II design. Eligibility criteria included pathologically proven ATC; unresectable measurable lesion as defined by RECIST 1.1; age 20 years or older; ECOG PS 0-2; and adequate organ function. The primary end-point was overall survival. Secondary end-points were progression-free survival, objective response rate, disease control rate, clinical benefit rate, and safety.
RESULTS: Of 52 patients enrolled from 17 institutions, 42 patients who were confirmed to have ATC were included for efficacy analysis, and 50 patients were included for safety analysis. The estimated 1-year overall survival rate was 11.9% (95% CI, 4.4%-23.6%). One patient (2.4%) achieved complete response, four patients (9.5%) partial response, and 26 patients (61.9%) stable disease, including nine patients (21.4%) who demonstrated durable stable disease, giving an objective response rate of 11.9%, disease control rate of 73.8%, and clinical benefit rate of 33.3%. Adverse events of any grade were observed in 45 patients (90.0%), the most common of which of any grade included loss of appetite (48.0%), fatigue (48.0%), hypertension (44.0%), and palmar-plantar erythrodysesthesia syndrome (26.0%).
CONCLUSION: Lenvatinib treatment resulted in disappointing survival for unresectable ATC patients. Although the number of responders was small, responses were durable, indicating that lenvatinib may be beneficial for selected patients. Further investigation to identify suitable candidates for lenvatinib monotherapy is needed.

Copyright © 2022 Elsevier Ltd. All rights reserved.
PMID 35932627
A Miyauchi, F Matsuzuka, K Hirai, T Yokozawa, K Kobayashi, S Kuma, K Kuma, H Futami, K Yamaguchi
Unilateral surgery supported by germline RET oncogene mutation analysis in patients with sporadic medullary thyroid carcinoma.
World J Surg. 2000 Nov;24(11):1367-72. doi: 10.1007/s002680010226.
Abstract/Text Compared to hereditary medullary thyroid carcinoma (MTC), sporadic MTC tends to be unicentric and confined to one lobe. Patients with sporadic MTC usually undergo total thyroidectomy because of a possible hereditary or bilateral process. We evaluated the usefulness of germline RET oncogene mutation analysis in surgery for apparently sporadic MTC and performed unilateral surgery on patients without detectable mutation. In 36 patients with a preoperative diagnosis of apparently sporadic MTC, we performed germline RET oncogene mutation analyses: before surgery in 8 recent patients and after surgery in 28 who had been treated before 1996. Of the latter, 5 had bilateral MTC. DNA samples were extracted from their peripheral blood, and the polymerase chain reaction products of the RET proto-oncogene were analyzed using single-strand conformation polymorphism analysis and the direct sequencing methods. Before 1996 we often performed total thyroidectomy but changed to hemithyroidectomy thereafter, except in one patient with associated Graves' ophthalmopathy. Our minimal standard practice included systematic central and ipsilateral neck dissection. The outcome was assessed in terms of gastrin- and calcium-stimulated plasma calcitonin levels. Germline RET mutations were found in six patients. Five of these patients had bilateral MTC, whereas all 30 patients without mutation had unilateral disease. Hemithyroidectomy in seven of our recent patients resulted in normalization of plasma calcitonin levels in all, although four were found to have microscopic lymph node involvement. In conclusion, hemithyroidectomy with systematic central and ipsilateral neck dissection is an appropriate procedure for patients with sporadic MTC without detectable germline RET mutations.

PMID 11038208
Sophie Leboulleux, Claire Bournaud, Cecile N Chougnet, Slimane Zerdoud, Abir Al Ghuzlan, Bogdan Catargi, Christine Do Cao, Antony Kelly, Marie-Luce Barge, Ludovic Lacroix, Inna Dygai, Pierre Vera, Daniela Rusu, Olivier Schneegans, Danielle Benisvy, Marc Klein, Julie Roux, Marie-Claude Eberle, Delphine Bastie, Camila Nascimento, Anne-Laure Giraudet, Nathalie Le Moullec, Stéphane Bardet, Delphine Drui, Nathalie Roudaut, Yann Godbert, Olivier Morel, Anne Drutel, Livia Lamartina, Claire Schvartz, Fritz-Line Velayoudom, Martin-Jean Schlumberger, Laurence Leenhardt, Isabelle Borget
Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer.
N Engl J Med. 2022 Mar 10;386(10):923-932. doi: 10.1056/NEJMoa2111953.
Abstract/Text BACKGROUND: In patients with low-risk differentiated thyroid cancer undergoing thyroidectomy, the postoperative administration of radioiodine (iodine-131) is controversial in the absence of demonstrated benefits.
METHODS: In this prospective, randomized, phase 3 trial, we assigned patients with low-risk differentiated thyroid cancer who were undergoing thyroidectomy to receive ablation with postoperative administration of radioiodine (1.1 GBq) after injections of recombinant human thyrotropin (radioiodine group) or to receive no postoperative radioiodine (no-radioiodine group). The primary objective was to assess whether no radioiodine therapy was noninferior to radioiodine therapy with respect to the absence of a composite end point that included functional, structural, and biologic abnormalities at 3 years. Noninferiority was defined as a between-group difference of less than 5 percentage points in the percentage of patients who did not have events that included the presence of abnormal foci of radioiodine uptake on whole-body scanning that required subsequent treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or elevated levels of thyroglobulin or thyroglobulin antibodies. Secondary end points included prognostic factors for events and molecular characterization.
RESULTS: Among 730 patients who could be evaluated 3 years after randomization, the percentage of patients without an event was 95.6% (95% confidence interval [CI], 93.0 to 97.5) in the no-radioiodine group and 95.9% (95% CI, 93.3 to 97.7) in the radioiodine group, a difference of -0.3 percentage points (two-sided 90% CI, -2.7 to 2.2), a result that met the noninferiority criteria. Events consisted of structural or functional abnormalities in 8 patients and biologic abnormalities in 23 patients with 25 events. Events were more frequent in patients with a postoperative serum thyroglobulin level of more than 1 ng per milliliter during thyroid hormone treatment. Molecular alterations were similar in patients with or without an event. No treatment-related adverse events were reported.
CONCLUSIONS: In patients with low-risk thyroid cancer undergoing thyroidectomy, a follow-up strategy that did not involve the use of radioiodine was noninferior to an ablation strategy with radioiodine regarding the occurrence of functional, structural, and biologic events at 3 years. (Funded by the French National Cancer Institute; ESTIMABL2 ClinicalTrials.gov number, NCT01837745.).

Copyright © 2022 Massachusetts Medical Society.
PMID 35263518
C Durante, N Haddy, E Baudin, S Leboulleux, D Hartl, J P Travagli, B Caillou, M Ricard, J D Lumbroso, F De Vathaire, M Schlumberger
Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy.
J Clin Endocrinol Metab. 2006 Aug;91(8):2892-9. doi: 10.1210/jc.2005-2838. Epub 2006 May 9.
Abstract/Text AIM: The goal of this study was to estimate the cumulative activity of (131)I to be administered to patients with distant metastases from thyroid carcinoma.
METHODS: A total of 444 patients were treated from 1953-1994 for distant metastases from papillary and follicular thyroid carcinoma: 223 had lung metastases only, 115 had bone metastases only, 82 had both lung and bone metastases, and 24 had metastases at other sites. Treatment consisted of the administration of 3.7 GBq (100 mCi) (131)I after withdrawal of thyroid hormone treatment, every 3-9 months during the first 2 yr and then once a year until the disappearance of any metastatic uptake. Thyroxine treatment was given at suppressive doses between (131)I treatment courses.
RESULTS: Negative imaging studies (negative total body (131)I scans and conventional radiographs) were attained in 43% of the 295 patients with (131)I uptake; more frequently in those who were younger, had well-differentiated tumors, and had a limited extent of disease. Most negative studies (96%) were obtained after the administration of 3.7-22 GBq (100-600 mCi). Almost half of negative studies were obtained more than 5 yr after the initiation of the treatment of metastases. Among patients who achieved a negative study, only 7% experienced a subsequent tumor recurrence. Overall survival at 10 yr after initiation of (131)I treatment was 92% in patients who achieved a negative study and 19% in those who did not.
CONCLUSION: (131)I treatment is highly effective in younger patients with (131)I uptake and with small metastases. They should be treated until the disappearance of any uptake or until a cumulative activity of 22 GBq has been administered. In the other patients, other treatment modalities should be used when tumor progression has been documented.

PMID 16684830
Yasuhiro Ito, Naoyoshi Onoda, Ken-Ichi Ito, Iwao Sugitani, Shunji Takahashi, Iku Yamaguchi, Koki Kabu, Katsuya Tsukada
Sorafenib in Japanese Patients with Locally Advanced or Metastatic Medullary Thyroid Carcinoma and Anaplastic Thyroid Carcinoma.
Thyroid. 2017 Sep;27(9):1142-1148. doi: 10.1089/thy.2016.0621. Epub 2017 Jul 24.
Abstract/Text BACKGROUND: Therapeutic options for treating advanced or metastatic medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC) are still limited in Japan, even though vandetanib for MTC and lenvatinib for MTC and ATC have been approved. Sorafenib is an oral multikinase inhibitor approved for the treatment of patients with radioactive iodine-refractory differentiated thyroid cancer (DTC). An uncontrolled, open-label, multicenter, single-arm, Phase 2 clinical study was conducted to evaluate the safety and efficacy of sorafenib in Japanese patients with MTC and ATC.
METHODS: Japanese patients with histologically confirmed ATC and locally advanced or metastatic MTC were enrolled from April to September 2014. The primary endpoint was to evaluate the safety of sorafenib. Treatment efficacy variables including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and maximum reduction in tumor size were evaluated as secondary endpoints. Patients received sorafenib 400 mg orally twice daily on a continuous basis and then continued treatment until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent.
RESULTS: A total of 20 patients were screened, and 18 (8 with MTC and 10 with ATC) were enrolled. The most common drug-related adverse events were palmar-plantar erythrodysesthesia (72%), alopecia (56%), hypertension (56%), and diarrhea (44%). In the ATC patients, median PFS was 2.8 months [confidence interval 0.7-5.6], and median OS was 5.0 months [confidence interval 0.7-5.7]; ORR and DCR were 0% and 40%, respectively. In the MTC population, neither median PFS nor OS had been reached at the time of this analysis; ORR was 25% and DCR was 75%.
CONCLUSIONS: The toxicities reported in this study were consistent with the known safety profile of sorafenib. Sorafenib seems to be effective in the treatment of advanced MTC but not ATC, and could be a new treatment option for locally advanced or metastatic MTC and radioactive iodine-refractory DTC.

PMID 28635560
Samuel A Wells, Jessica E Gosnell, Robert F Gagel, Jeffrey Moley, David Pfister, Julie A Sosa, Michael Skinner, Annetta Krebs, James Vasselli, Martin Schlumberger
Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer.
J Clin Oncol. 2010 Feb 10;28(5):767-72. doi: 10.1200/JCO.2009.23.6604. Epub 2010 Jan 11.
Abstract/Text PURPOSE There is no effective therapy for patients with distant metastasis of medullary thyroid carcinoma (MTC). Activating mutations in the RET proto-oncogene cause hereditary MTC, which provides a strong therapeutic rationale for targeting RET kinase activity. This open-label, phase II study assessed the efficacy of vandetanib, a selective oral inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, in patients with advanced hereditary MTC. METHODS Patients with unresectable locally advanced or metastatic hereditary MTC received initial treatment with once-daily oral vandetanib 300 mg. The dose was adjusted additionally in some patients on the basis of observed toxicity until disease progression or any other withdrawal criterion was met. The primary assessment was objective tumor response (by RECIST [Response Evaluation Criteria in Solid Tumors]). Results Thirty patients received initial treatment with vandetanib 300 mg/d. On the basis of investigator assessments, 20% of patients (ie, six of 30 patients) experienced a confirmed partial response (median duration of response at data cutoff, 10.2 months). An additional 53% of patients (ie, 16 of 30 patients) experienced stable disease at >/= 24 weeks, which yielded a disease control rate of 73% (ie, 22 of 30 patients). In 24 patients, serum calcitonin levels showed a 50% or greater decrease from baseline that was maintained for at least 4 weeks; 16 patients showed a similar reduction in serum carcinoembryonic antigen levels. The most common adverse events were diarrhea (70%), rash (67%), fatigue (63%), and nausea (63%). CONCLUSION In this study, vandetanib demonstrated durable objective partial responses and disease control with a manageable adverse event profile. These results demonstrate that vandetanib may provide an effective therapeutic option in patients with advanced hereditary MTC, a rare disease for which there has been no effective therapy.

PMID 20065189
Makoto Tahara, Naomi Kiyota, Tomoko Yamazaki, Naoko Chayahara, Kenji Nakano, Lina Inagaki, Kazuhisa Toda, Tomohiro Enokida, Hironobu Minami, Yoshinori Imamura, Tatsuya Sasaki, Takuya Suzuki, Katsuki Fujino, Corina E Dutcus, Shunji Takahashi
Lenvatinib for Anaplastic Thyroid Cancer.
Front Oncol. 2017;7:25. doi: 10.3389/fonc.2017.00025. Epub 2017 Mar 1.
Abstract/Text BACKGROUND: Lenvatinib has been approved by regulatory agencies in Japan, the United States, and the European Union for treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thyroid cancer, however, is a clinically diverse disease that includes anaplastic thyroid cancer (ATC), the subtype associated with the highest lethality. Effective therapy for ATC is an unmet need.
PATIENTS AND METHODS: This phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate.
RESULTS: At data cutoff, 17 patients with ATC were enrolled. All experienced ≥1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were decreased appetite (82%), hypertension (82%), fatigue (59%), nausea (59%), and proteinuria (59%). Of note, only one patient required lenvatinib withdrawal because of a TEAE, and this TEAE was considered unrelated to lenvatinib. The median PFS was 7.4 months [95% confidence interval (CI): 1.7-12.9], the median OS was 10.6 months (95% CI: 3.8-19.8), and the objective response rate was 24%.
CONCLUSION: In this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC.
CLINICALTRIALSGOV: NCT01728623.

PMID 28299283
Steven G Waguespack, Alexander Drilon, Jessica J Lin, Marcia S Brose, Ray McDermott, Mohammed Almubarak, Jessica Bauman, Michela Casanova, Anuradha Krishnamurthy, Shivaani Kummar, Serge Leyvraz, Do-Youn Oh, Keunchil Park, Davendra Sohal, Eric Sherman, Ricarda Norenberg, Josh D Silvertown, Nicoletta Brega, David S Hong, Maria E Cabanillas
Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma.
Eur J Endocrinol. 2022 Apr 29;186(6):631-643. doi: 10.1530/EJE-21-1259. Epub 2022 Apr 29.
Abstract/Text Objective: Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC).
Methods: We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020.
Results: Twenty-nine patients (median age: 60; range: 6-80) with TRK fusion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51-87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. ORR was 86% (95% CI: 64-97) for PTC/FTC and 29% (95% CI 4-71) for ATC. Median time to response was 1.87 months (range 1.64-3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adverse events were mainly grades 1-2.
Conclusion: In TRK fusion-positive TC, larotrectinib demonstrates rapid and durable disease control and a favourable safety profile in patients with advanced disease requiring systemic therapy.
Significance statement: NTRK gene fusions are known oncogenic drivers and have been identified in various histologies of thyroid carcinoma, most commonly in papillary thyroid carcinoma. This is the first publication specifically studying a TRK inhibitor in a cohort of TRK fusion-positive thyroid carcinoma patients. In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK fusion-positive thyroid carcinoma. Our findings show that patients with advanced non-medullary thyroid carcinoma who may require systemic therapy could be considered for testing for gene fusions by next-generation sequencing.

PMID 35333737
David S Hong, Steven G DuBois, Shivaani Kummar, Anna F Farago, Catherine M Albert, Kristoffer S Rohrberg, Cornelis M van Tilburg, Ramamoorthy Nagasubramanian, Jordan D Berlin, Noah Federman, Leo Mascarenhas, Birgit Geoerger, Afshin Dowlati, Alberto S Pappo, Stefan Bielack, François Doz, Ray McDermott, Jyoti D Patel, Russell J Schilder, Makoto Tahara, Stefan M Pfister, Olaf Witt, Marc Ladanyi, Erin R Rudzinski, Shivani Nanda, Barrett H Childs, Theodore W Laetsch, David M Hyman, Alexander Drilon
Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.
Lancet Oncol. 2020 Apr;21(4):531-540. doi: 10.1016/S1470-2045(19)30856-3. Epub 2020 Feb 24.
Abstract/Text BACKGROUND: The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.
METHODS: Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).
FINDINGS: Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred.
INTERPRETATION: These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible.
FUNDING: Bayer and Loxo Oncology.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32105622
Manju L Prasad, Monika Vyas, Matthew J Horne, Renu K Virk, Raffaella Morotti, Zongzhi Liu, Giovanni Tallini, Marina N Nikiforova, Emily R Christison-Lagay, Robert Udelsman, Catherine A Dinauer, Yuri E Nikiforov
NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States.
Cancer. 2016 Apr 1;122(7):1097-107. doi: 10.1002/cncr.29887. Epub 2016 Jan 19.
Abstract/Text BACKGROUND: An increase in thyroid cancers, predominantly papillary thyroid carcinoma (PTC), has been recently reported in children.
METHODS: The histopathology of 28 consecutive PTCs from the northeast United States was reviewed. None of the patients (ages 6-18 years; 20 females, 8 males) had significant exposure to radiation. Nucleic acid from tumors was tested for genetic abnormalities (n = 27). Negative results were reevaluated by targeted next-generation sequencing.
RESULTS: Seven of 27 PTCs (26%) had neurotrophic tyrosine kinase receptor (NTRK) fusion oncogenes (NTRK type 3/ets variant 6 [NTRK3/ETV6], n =5; NTRK3/unknown, n = 1; and NTRK type 1/translocated promoter region, nuclear basket protein [NTRK1/TPR], n = 1), including 5 tumors that measured >2 cm and 3 that diffusely involved the entire thyroid or lobe. All 7 tumors had lymphatic invasion, and 5 had vascular invasion. Six of 27 PTCs (22%) had ret proto-oncogene (RET) fusions (RET/PTC1, n = 5; RET/PTC3, n = 1); 2 tumors measured >2 cm and diffusely involved the thyroid, and 5 had lymphatic invasion, with vascular invasion in 2. Thirteen PTCs had the B-Raf proto-oncogene, serine/threonine kinase (BRAF) valine-to-glutamic acid mutation at position 600 (BRAF(V) (600E)) (13 of 27 tumors; 48%), 11 measured <2 cm, and 6 had lymphatic invasion (46%), with vascular invasion in 3. Fusion oncogene tumors, compared with BRAF(V) (600E) PTCs, were associated with large size (mean, 2.2 cm vs 1.5 cm, respectively; P = .05), solid and diffuse variants (11 of 13 vs 0 of 13 tumors, respectively; P < .001), and lymphovascular invasion (12 of 13 vs 6 of 13 tumors, respectively; P = .02); BRAF(V) (600E) PTCs were predominantly the classic variant (12 of 13 vs 1 of 13 tumors). Two tumors metastasized to the lung, and both had fusion oncogenes (NTRK1/TPR, n = 1; RET/PTC1, n = 1).
CONCLUSIONS: Fusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAF(V) (600E) PTC in the pediatric population. The high prevalence of the NTRK1/NTRK3 fusion oncogene PTCs in the United States is unusual and needs further investigation.

© 2016 American Cancer Society.
PMID 26784937
Ryosuke Okamura, Amélie Boichard, Shumei Kato, Jason K Sicklick, Lyudmila Bazhenova, Razelle Kurzrock
Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics.
JCO Precis Oncol. 2018;2018. doi: 10.1200/PO.18.00183. Epub 2018 Nov 15.
Abstract/Text PURPOSE: Fusions that involve neurotrophic-tropomyosin receptor kinase (NTRK) genes are known drivers of oncogenesis. Therapies that target these ultra-rare, constitutionally active NTRK fusions have been remarkably effective. Herein, we analyze the prevalence of the full array of NTRK alterations-fusions, mutations, copy number alterations, and increased transcript expression-in diverse adult and pediatric tumor types to understand the landscape of NTRK aberrations in cancer.
METHODS: We assessed 13,467 samples available from The Cancer Genome Atlas (adult tumors) and the St Jude PeCan database (pediatric tumors) for the prevalence of NTRK fusions, as well as associated genomic and transcriptomic co-aberrations in different tumor types.
RESULTS: NTRK fusions were observed in 0.31% of adult tumors and in 0.34% of pediatric tumors. The most common gene partners were NTRK3 (0.16% of adult tumors) followed by NTRK1 (0.14% of pediatric tumors). NTRK fusions were found more commonly in pediatric melanoma (11.1% of samples), pediatric glioma (3.97%), and adult thyroid cancers (2.34%). Additional genomic and transcriptomic NTRK alterations- mutation, amplification, and mRNA overexpression-occurred in 14.2% of samples, whereas the frequency of alterations that implicated NTRK ligands and the NTRK co-receptor (p75NTR) ranged from 3.8% to 5.4%. Among 31 adult samples carrying NTRK fusions, co-alterations occurred often and usually involved the downstream phosphoinositide-3-kinase signaling pathway, cell-cycle machinery, other tyrosine-kinase receptors, and mitogen-activated protein kinase signals.
CONCLUSION: Whereas NTRK fusions are exceedingly rare, other NTRK abnormalities affect 14% of patients with cancer. Affecting these alterations has not yet been achievable in cancer. Genomic co-alterations occur frequently with NTRK fusions, but it is not known if co-targeting them can attenuate primary or secondary resistance to NTRK inhibitors.

PMID 30637364
Lori J Wirth, Eric Sherman, Bruce Robinson, Benjamin Solomon, Hyunseok Kang, Jochen Lorch, Francis Worden, Marcia Brose, Jyoti Patel, Sophie Leboulleux, Yann Godbert, Fabrice Barlesi, John C Morris, Taofeek K Owonikoko, Daniel S W Tan, Oliver Gautschi, Jared Weiss, Christelle de la Fouchardière, Mark E Burkard, Janessa Laskin, Matthew H Taylor, Matthias Kroiss, Jacques Medioni, Jonathan W Goldman, Todd M Bauer, Benjamin Levy, Viola W Zhu, Nehal Lakhani, Victor Moreno, Kevin Ebata, Michele Nguyen, Dana Heirich, Edward Y Zhu, Xin Huang, Luxi Yang, Jennifer Kherani, S Michael Rothenberg, Alexander Drilon, Vivek Subbiah, Manisha H Shah, Maria E Cabanillas
Efficacy of Selpercatinib in RET-Altered Thyroid Cancers.
N Engl J Med. 2020 Aug 27;383(9):825-835. doi: 10.1056/NEJMoa2005651.
Abstract/Text BACKGROUND: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.
METHODS: We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.
RESULTS: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.
CONCLUSIONS: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32846061
V Subbiah, R J Kreitman, Z A Wainberg, J Y Cho, J H M Schellens, J C Soria, P Y Wen, C C Zielinski, M E Cabanillas, A Boran, P Ilankumaran, P Burgess, T Romero Salas, B Keam
Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study.
Ann Oncol. 2022 Apr;33(4):406-415. doi: 10.1016/j.annonc.2021.12.014. Epub 2022 Jan 10.
Abstract/Text BACKGROUND: Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up.
PATIENTS AND METHODS: ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS: At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib.
CONCLUSIONS: These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.
PMID 35026411
Jennifer R Wang, Mark E Zafereo, Ramona Dadu, Renata Ferrarotto, Naifa L Busaidy, Charles Lu, Salmaan Ahmed, Maria K Gule-Monroe, Michelle D Williams, Erich M Sturgis, Ryan P Goepfert, Neil D Gross, Stephen Y Lai, Gary Brandon Gunn, Jack Phan, David I Rosenthal, Clifton David Fuller, William H Morrison, Priyanka Iyer, Maria E Cabanillas
Complete Surgical Resection Following Neoadjuvant Dabrafenib Plus Trametinib in BRAFV600E-Mutated Anaplastic Thyroid Carcinoma.
Thyroid. 2019 Aug;29(8):1036-1043. doi: 10.1089/thy.2019.0133.
Abstract/Text Background: When achieved, complete surgical resection improves outcomes in anaplastic thyroid carcinoma (ATC). However, most ATC patients present with advanced inoperable disease, often with impending airway obstruction, increased hemorrhage risk, and significant dysphagia. Novel treatment strategies are critically needed to improve disease control and decrease locoregional morbidity. The objective of this study was to determine the feasibility and effectiveness of a neoadjuvant regimen by using dabrafenib with trametinib followed by surgical resection in patients with initially unresectable BRAFV600E-mutated ATC. Methods: Case series of six consecutive patients with BRAFV600E-mutated ATC diagnosed between January 2017 and February 2018. Pathologic confirmation of ATC was obtained before treatment. BRAFV600E status was ascertained via immunohistochemistry or sequencing of circulating tumor DNA. All patients received dabrafenib and trametinib (DT) followed by surgical resection and adjuvant chemoradiation. Three patients also received pembrolizumab. Results: Complete surgical resection was achieved in all patients. Histopathologic analyses of resected specimens showed high pathologic response rates with significantly decreased ATC viability and residual papillary thyroid carcinoma components. Overall survival at six months and one year was 100% and 83%, respectively. Locoregional control rate was 100%. Two patients died of distant metastases without evidence of locoregional disease at 8 and 14 months from diagnosis. The remaining four patients had no evidence of disease at the last follow-up. Conclusions: We report the first series in the literature of BRAFV600E-mutated ATC patients with locoregionally advanced disease treated with DT followed by surgical resection. We demonstrated feasibility of complete resection, decreased need for tracheostomy, high pathologic response rates, and durable locoregional control with symptom amelioration.

PMID 31319771
Vivek Subbiah, Robert J Kreitman, Zev A Wainberg, Jae Yong Cho, Jan H M Schellens, Jean Charles Soria, Patrick Y Wen, Christoph Zielinski, Maria E Cabanillas, Gladys Urbanowitz, Bijoyesh Mookerjee, Dazhe Wang, Fatima Rangwala, Bhumsuk Keam
Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer.
J Clin Oncol. 2018 Jan 1;36(1):7-13. doi: 10.1200/JCO.2017.73.6785. Epub 2017 Oct 26.
Abstract/Text Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E-mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.

PMID 29072975
Maria E Cabanillas, Renata Ferrarotto, Adam S Garden, Salmaan Ahmed, Naifa L Busaidy, Ramona Dadu, Michelle D Williams, Heath Skinner, G Brandon Gunn, Horiana Grosu, Priyanka Iyer, Marie Claude Hofmann, Mark Zafereo
Neoadjuvant BRAF- and Immune-Directed Therapy for Anaplastic Thyroid Carcinoma.
Thyroid. 2018 Jul;28(7):945-951. doi: 10.1089/thy.2018.0060. Epub 2018 Jun 29.
Abstract/Text Anaplastic thyroid cancer (ATC) is a devastating disease with a dismal prognosis. Patients who have disease confined to the thyroid and who are able to undergo complete surgery and chemoradiation stand the best chance for survival. Unfortunately, nearly 50% of patients have distant metastases at diagnosis, and most present with locally advanced, unresectable tumors. Nevertheless, BRAF-mutated ATC patients represent a subset of cases who can benefit from a combination therapy with BRAF and MEK inhibitors. Here, a patient is presented with end-stage, locally advanced, unresectable ATC who was treated with this combination. Immunotherapy with pembrolizumab was added at the first sign of progression after which he achieved a partial response to therapy, enabling a complete surgical resection followed by postoperative chemoradiation to be undertaken. This novel neoadjuvant approach to BRAF-mutated ATC should be studied in further in clinical trials.

PMID 29742974
Bryan R Haugen, Erik K Alexander, Keith C Bible, Gerard M Doherty, Susan J Mandel, Yuri E Nikiforov, Furio Pacini, Gregory W Randolph, Anna M Sawka, Martin Schlumberger, Kathryn G Schuff, Steven I Sherman, Julie Ann Sosa, David L Steward, R Michael Tuttle, Leonard Wartofsky
2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer.
Thyroid. 2016 Jan;26(1):1-133. doi: 10.1089/thy.2015.0020.
Abstract/Text BACKGROUND: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer.
METHODS: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members.
RESULTS: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research.
CONCLUSIONS: We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

PMID 26462967
Osamu Fukuoka, Iwao Sugitani, Aya Ebina, Kazuhisa Toda, Kazuyoshi Kawabata, Keiko Yamada
Natural History of Asymptomatic Papillary Thyroid Microcarcinoma: Time-Dependent Changes in Calcification and Vascularity During Active Surveillance.
World J Surg. 2016 Mar;40(3):529-37. doi: 10.1007/s00268-015-3349-1.
Abstract/Text BACKGROUND: Prospective trials of non-surgical observation have shown progression rates of only 5-10% in patients with asymptomatic papillary microcarcinoma (PMC). This study investigated time-dependent changes in calcification patterns and tumor vascularity on ultrasonography (US) to clarify the natural course of PMC.
METHODS: We examined calcification patterns and tumor vascularity for 480 lesions in 384 patients. Calcification patterns were classified as: (A) none; (B) micro; (C) macro; or (D) rim. Tumor vascularity was classified as rich or poor via color Doppler US.
RESULTS: After a mean of 6.8 years of observation, 29 lesions (6.0%) had increased in size. Mean age for initial calcification pattern was 52.1 years for A (n = 135), 54.2 years for B (n = 235), 56.3 years for C (n = 96), and 60.1 years for D (n = 14), and the incidence rates of tumor enlargement were 9.6, 5.5, 3.2, and 0%, respectively. The cumulative rate of upgrade in calcification pattern was 51.8% at 10 years. Lesions with initially rich vascularity (n = 70) had significantly higher rate of tumor enlargement than those with poor vascularity (n = 410); however, the majority of tumor (61.4%) with initially rich vascularity had decreased their blood supply during the follow-up. Multivariate analysis showed that strong calcification (C or D) and poor vascularity at last examination correlated significantly with non-progressive disease.
CONCLUSIONS: PMCs in older patients showed significantly stronger calcification patterns and poorer vascularity. Both consolidation of calcification and loss of vascularity occurred in a time-dependent manner during observation and were significant indicators for non-progressive disease.

PMID 26581368

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