今日の臨床サポート

甲状腺癌 乳頭癌

著者: 宮内昭 神甲会隈病院

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:2021/07/07
患者向け説明資料

概要・推奨   

  1. 甲状腺結節について
  1. 甲状腺結節の鑑別診断において、現在最も有用であるのは超音波検査と穿刺吸引細胞診である。穿刺吸引細胞診の適応としては、日本乳腺甲状腺超音波医学会では、超音波所見により、充実性腫瘍は>5mmの強く悪性を疑う腫瘤、>10mmの悪性を疑う腫瘤、>20mmの腫瘤、嚢胞性腫瘤は>20mmの腫瘤としている。嚢包・充実の混合する場合は充実部分の所見を優先して適応を決める(推奨度2)。なお参考として、アメリカ甲状腺学会では1cm未満の腫瘤はリンパ節転移や周囲組織への浸潤などの進行性の所見がなければ細胞診は必要ではないとしている。これは過剰診断・過剰治療を避けるためである。
  1. 甲状腺結節の鑑別診断の目的としては超音波検査を行うことを強く推奨する(推奨度1)が、CT、MRI、FDG-PETは行わないことを推奨する(推奨度3)。
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  1. 甲状腺髄様癌患者に対しては、すべてのの患者にRET遺伝学的検査を行うことを推奨する(推奨度1)。
  1. 未発症RET変異保有者に対して一律に予報的甲状腺全摘を行うことは推奨しない(推奨度3)。
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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。
※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、実際の保険適用の査定において保険適用及び保険適用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用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:
宮内昭 : 特に申告事項無し[2021年]
監修:平田結喜緒 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 日本内分泌外科学会と日本甲状腺外科学会が2010年に公開した「甲状腺腫瘍診療ガイドライン」が2018年に改訂された。新たに蓄積されたエビデンスがあり、外来での放射性ヨウ素内用療法や分子標的薬などの治療方法に対応し、主要な甲状腺悪性腫瘍である乳頭癌、濾胞癌、髄様癌、および未分化癌に対して、リスク分類や進行度に応じて望ましい管理方針をフローチャートで分かりやすく示している。なお、両学会は合併し、新たな日本内分泌外科学会となっている。このガイドラインの改定に基づき記載を全面的に加筆修正した。

病態・疫学・診察

疾患情報  
  1. わが国における甲状腺癌罹患率は徐々に増加しており、2019年の国立がん研究センターの報告によると、2015年における甲状腺癌罹患数は15,075人、うち男性4,055人、女性11,020人であり、男女比は1:2.7と女性に多く、甲状腺癌による死亡数は1,731人、うち男性586人、女性1,145人であったとのことである[1]
  1. 参照:全国がん罹患モニタニング集計 2015年罹患数・率報告
  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]。増加したのは乳頭癌であり、濾胞癌、髄様癌、未分化癌などほかの甲状腺癌の増加はなく、乳頭癌の中でも2cm以下あるいは1cm以下(微小乳頭癌という)が増加し、大きい乳頭癌は増加していなかった[3]。これらのことから、超音波検査やCTスキャンなどの画像検査の普及による無症候性の小さい乳頭癌の過剰診断・過剰治療が問題となっている[2][3]。ただし、発生率の増加を示唆する報告もある。
  1. 小児期の放射線被曝は、明らかなリスク因子である[4]
  1. ヨウ素摂取量と生じる甲状腺癌の種類には関連性がある。ヨウ素摂取量が少ない地域では濾胞癌が多く、多い地域では乳頭癌が多い。甲状腺悪性腫瘍の約90%は乳頭癌、約5%が濾胞癌であり、低分化癌、未分化癌、髄様癌、悪性リンパ腫がそれぞれ1~2%である。甲状腺悪性腫瘍は病理組織型によって種々の臨床像が異なり、したがって適切な治療方法も予後も異なるので、治療開始前に病理組織型診断をつけることが必要である。それぞれの腫瘍の特徴を簡潔に示す。
 
甲状腺悪性腫瘍の病理組織型別の特徴

US:超音波検査
FNA:穿刺吸引細胞診、RAI:放射性ヨウ素内用療法
TKI:チロシンキナーゼ阻害薬
(手術):悪性リンパ腫における手術の第1目的は診断をつけることである。

出典

img1:  著者提供
 
 
問診・診察のポイント  
  1. 発見の契機と発見者、症状(嗄声、呼吸困難、嚥下障害、疼痛など)、腫瘤の大きさの変化、家族歴、放射線被曝歴が問診の主要項目である。

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文献 

著者: Louise Davies, H Gilbert Welch
雑誌名: JAMA Otolaryngol Head Neck Surg. 2014 Apr;140(4):317-22. doi: 10.1001/jamaoto.2014.1.
Abstract/Text IMPORTANCE: We have previously reported on a doubling of thyroid cancer incidence-largely due to the detection of small papillary cancers. Because they are commonly found in people who have died of other causes, and because thyroid cancer mortality had been stable, we argued that the increased incidence represented overdiagnosis.
OBJECTIVE: To determine whether thyroid cancer incidence has stabilized.
DESIGN: Analysis of secular trends in patients diagnosed with thyroid cancer, 1975 to 2009, using the Surveillance, Epidemiology, and End Results (SEER) program and thyroid cancer mortality from the National Vital Statistics System.
SETTING: Nine SEER areas (SEER 9): Atlanta, Georgia; Connecticut; Detroit, Michigan; Hawaii; Iowa; New Mexico; San Francisco-Oakland, California; Seattle-Puget Sound, Washington; and Utah.
PARTICIPANTS: Men and women older than 18 years diagnosed as having a thyroid cancer between 1975 and 2009 who lived in the SEER 9 areas.
INTERVENTIONS: None.
MAIN OUTCOMES AND MEASURES: Thyroid cancer incidence, histologic type, tumor size, and patient mortality. RESULTS Since 1975, the incidence of thyroid cancer has now nearly tripled, from 4.9 to 14.3 per 100,000 individuals (absolute increase, 9.4 per 100,000; relative rate [RR], 2.9; 95% CI, 2.7-3.1). Virtually the entire increase was attributable to papillary thyroid cancer: from 3.4 to 12.5 per 100,000 (absolute increase, 9.1 per 100,000; RR, 3.7; 95% CI, 3.4-4.0). The absolute increase in thyroid cancer in women (from 6.5 to 21.4 = 14.9 per 100,000 women) was almost 4 times greater than that of men (from 3.1 to 6.9 = 3.8 per 100,000 men). The mortality rate from thyroid cancer was stable between 1975 and 2009 (approximately 0.5 deaths per 100,000).
CONCLUSIONS AND RELEVANCE: There is an ongoing epidemic of thyroid cancer in the United States. The epidemiology of the increased incidence, however, suggests that it is not an epidemic of disease but rather an epidemic of diagnosis. The problem is particularly acute for women, who have lower autopsy prevalence of thyroid cancer than men but higher cancer detection rates by a 3:1 ratio.

PMID 24557566  JAMA Otolaryngol Head Neck Surg. 2014 Apr;140(4):317-22・・・
著者: Louise Davies, H Gilbert Welch
雑誌名: 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  JAMA. 2006 May 10;295(18):2164-7. doi: 10.1001/jama.295・・・
著者: E Ron, J H Lubin, R E Shore, K Mabuchi, B Modan, L M Pottern, A B Schneider, M A Tucker, J D Boice
雑誌名: 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  Radiat Res. 1995 Mar;141(3):259-77.
著者: D W ROBINSON, T G ORR
雑誌名: AMA Arch Surg. 1955 Jun;70(6):923-8.
Abstract/Text
PMID 14375516  AMA Arch Surg. 1955 Jun;70(6):923-8.
著者: Yasuhiro Ito, Kennichi Kakudo, Mitsuyoshi Hirokawa, Mitsuhiro Fukushima, Tomonori Yabuta, Chisato Tomoda, Hiroyuki Inoue, Minoru Kihara, Takuya Higashiyama, Takashi Uruno, Yuuki Takamura, Akihiro Miya, Kaoru Kobayashi, Fumio Matsuzuka, Akira Miyauchi
雑誌名: Surgery. 2009 Jan;145(1):100-5. doi: 10.1016/j.surg.2008.08.004. Epub 2008 Sep 21.
Abstract/Text BACKGROUND: Although the responsible genes have not yet been identified, it is known that the risk of nonmedullary thyroid carcinoma is elevated in individuals with 1st-degree relatives with nonmedullary thyroid carcinoma. However, it remains controversial whether the biological character of familial nonmedullary carcinoma (FNMTC) differs from that of sporadic carcinoma. In this study, we investigated the prevalence of familial papillary carcinoma and its biological behavior.
METHODS: Between 1987 and 2004, 6,015 patients underwent initial surgical treatment for papillary carcinoma at Kuma Hospital and 273 (4.5%) were classified as having familial carcinoma. We compared the biological characteristics including prognosis between familial and sporadic papillary carcinomas.
RESULTS: Disease-free survival and cause-specific survival rates of familial carcinoma did not differ from those of sporadic carcinoma. Familial papillary carcinoma showed multicentricity and recurrence to the thyroid more frequently than sporadic carcinoma. There were no differences in other clinicopathological parameters between the 2 groups.
CONCLUSION: Prognosis of patients with familial papillary carcinoma did not differ from that of those with sporadic papillary carcinoma. Although routine total thyroidectomy is recommended for familial papillary carcinoma, its therapeutic strategy can otherwise be the same as that for sporadic papillary carcinoma.

PMID 19081481  Surgery. 2009 Jan;145(1):100-5. doi: 10.1016/j.surg.200・・・
著者: T Yokozawa, A Miyauchi, K Kuma, M Sugawara
雑誌名: Thyroid. 1995 Apr;5(2):141-5.
Abstract/Text We describe an accurate and simple method of diagnosing thyroid nodules by the modified technique of ultrasound-guided fine needle aspiration biopsy (UG-FNAB). An Aloka SSD 2000 focus type scanner (Aloka Co., Tokyo, Japan) equipped with a 10-MHz mechanical sector probe and a 7.5-MHz convex probe was used. First, a clear picture of the thyroid gland was taken with the use of the 10-MHz probe to determine the abnormalities. Then, a 7.5-MHz probe (1.5 x 0.8 cm of surface area) was used to guide the needle perpendicularly to the neck. This method enabled us to obtain samples from nodules greater than 5 mm. We applied this technique to 1000 patients who had uncertain diagnosis by the conventional method of FNAB. The advantages of this method are as follows: (i) The use of a small probe (7.5 MHz) is most important, since a needle can be inserted by watching the monitor without an assistant. (ii) The biopsy site can be chosen precisely. (iii) Small thyroid cancers, i.e., 5 mm cancer, can be biopsied without any difficulty. (iv) A life-threatening anaplastic carcinoma can be diagnosed at an early stage. (v) An intraglandular metastasis to the opposite lobe can be detected. (vi) Cystic carcinoma, difficult to diagnose by FNAB, can be diagnosed accurately. This method is highly recommended for all clinicians who are currently doing FNAB.

PMID 7647575  Thyroid. 1995 Apr;5(2):141-5.
著者: Yasuhiro Ito, Nobuyuki Amino, Tamotsu Yokozawa, Hisashi Ota, Maki Ohshita, Nao Murata, Shinji Morita, Kaoru Kobayashi, Akira Miyauchi
雑誌名: Thyroid. 2007 Dec;17(12):1269-76. doi: 10.1089/thy.2007.0014.
Abstract/Text Ultrasonography is the most useful tool for detection and evaluation of thyroid nodules. In this study, we present our classification system for ultrasonographic evaluation, which has been routinely performed since 1995. Of 1244 nodules identified by ultrasonography in 900 patients, 1145 nodules demonstrating adequate specimens on fine-needle aspiration biopsy were enrolled in the study. We stratified these nodules into classes 1 to 5 with intermediate steps of 0.5 for classes 2 to 5. Nodules classified as 3.5 or greater were evaluated as malignant, those classified as 3 were evaluated as borderline, and those classified as 2.5 or lower were evaluated as benign. Of 233 nodules evaluated as malignant, 179 (76.8%) were cytologically confirmed as malignant. Furthermore, 145 of 159 nodules (91.2%) classified as 4 or greater were cytologically diagnosed as carcinoma. Of 710 nodules evaluated as benign, 683 (96.1%) were cytologically confirmed as benign. Two hundred fifty-five nodules of 210 patients were surgically resected and pathologically examined. In this series, the positive predictive value of ultrasonographic evaluation of malignancy was 97.2%. These findings suggest that our classification system is simple and useful to facilitate ultrasonographic evaluation of thyroid nodules.

PMID 17988196  Thyroid. 2007 Dec;17(12):1269-76. doi: 10.1089/thy.2007・・・
著者: Takeo Kawai, Eijun Nishihara, Takumi Kudo, Hisashi Ota, Shinji Morita, Kaoru Kobayashi, Mitsuru Ito, Sumihisa Kubota, Nobuyuki Amino, Akira Miyauchi
雑誌名: Thyroid. 2012 Mar;22(3):299-303. doi: 10.1089/thy.2011.0272. Epub 2012 Feb 2.
Abstract/Text BACKGROUND: Patients who have thyroidectomies for thyroid nodules that are suspected of being malignant, called here "main nodules," occasionally have second nodules, called here "accessory nodules" that are evaluated by ultrasonography (US) and fine-needle aspiration cytology (FNAC). Most accessory nodules are diagnosed as benign based on preoperative US and FNAC. To evaluate the accuracy of US and FNAC for a group of nodules which were likely to be mostly benign we evaluated procedures to diagnose accessory nodules.
PATIENTS AND METHODS: In a total of 643 patients who underwent thyroidectomy for their main nodules, 866 accessory nodules were evaluated by US and/or FNAC preoperatively. All were evaluated by histopathological examination postoperatively. Of the 866 accessory nodules, 501 were evaluated by US only and 365 were evaluated by US and FNAC.
RESULTS: While the 363 accessory nodules were diagnosed as malignant by histopathology, 235 nodules were malignant by US and histopathology and 115 nodules were malignant by FNAC and histopathology. Among the accessory nodules that were diagnosed as benign by histopathology, 7.2% were malignant by US, and 4.4% were malignant by FNAC. Among the accessory nodules that were diagnosed as benign by FNAC, 15.0% were malignant by histopathology. This was a significantly higher percentage than the value of 6.2% for the accessory nodules diagnosed as benign by US but malignant by histopathology. Accessory nodules with a benign cytology on FNAC that were malignant were significantly smaller than those with a benign cytology and histopathology. Among the 126 accessory nodules that were read as benign by both US and FNAC, only one (0.8%) was diagnosed as papillary thyroid carcinoma by histopathology.
CONCLUSION: These data suggest that diagnostic accuracy of benign nodules based on both US and cytological evaluation was supported by the evidence of high-level histopathological compatibility in accessory nodules. FNAC and US have a low but not negligible false-negative diagnostic rate. When FNAC is combined with US the false-negative rate is probably very low.

PMID 22300250  Thyroid. 2012 Mar;22(3):299-303. doi: 10.1089/thy.2011.・・・
著者: G Sangalli, G Serio, C Zampatti, M Bellotti, G Lomuscio
雑誌名: Cytopathology. 2006 Oct;17(5):245-50. doi: 10.1111/j.1365-2303.2006.00335.x.
Abstract/Text OBJECTIVE: We evaluated the efficacy of fine needle aspiration cytology (FNAC) of the thyroid in a series of 5469 lesions with histological control and studied the causes of, and the possibility of reducing the limitations of the method.
METHODS: FNAC was always performed by a pathologist under the guidance of a clinician, using a 22-gauge needle. Generally two aspirations were carried out, and usually four slides were obtained for each nodule; they were then stained with May-Grünwald-Giemsa and with Papanicolaou. The cytological diagnoses were classified in four groups: inadequate, benign, suspicious and malignant.
RESULTS: We obtained a complete sensitivity of 93.4%, a positive predictive value of malignancy of 98.6%, and a specificity of 74.9%. At histological control, the cytological diagnosis of Hurthle cell neoplasm corresponded to a significantly higher incidence of malignant neoplasms than the diagnosis of non-Hurthle cell follicular neoplasm (32.1% versus 15.5%). There were 66 false-negative findings, the main cause of diagnostic error (24 cases) being failure to recognize the follicular variant of papillary carcinoma. The number of inadequate FNACs was low (4.2%).
CONCLUSION: Our study confirmed the great efficacy of thyroid FNAC. A cytological diagnosis of Hurthle cell neoplasm should be considered an indicator of high risk. Awareness that failure to recognize the follicular variant of papillary carcinoma was the main problem in the interpretation of thyroid FNAC should lead to a decrease of false-negative diagnoses. The inadequate rate was very low, as it was the pathologist personally who performed the needle aspiration.

PMID 16961652  Cytopathology. 2006 Oct;17(5):245-50. doi: 10.1111/j.13・・・
著者: Jack Yang, Vicki Schnadig, Roberto Logrono, Patricia G Wasserman
雑誌名: Cancer. 2007 Oct 25;111(5):306-15. doi: 10.1002/cncr.22955.
Abstract/Text BACKGROUND: The Papanicolaou Society of Cytopathology recently proposed 6 diagnostic categories for the classification of thyroid fine-needle aspiration (FNA) cytology. Using these categories, the experience with FNA from 2 institutions was studied with emphasis on cytologic-histologic correlation, source of errors, and clinical management.
METHODS: Patient cytology data were retrieved by a retrospective search of thyroid FNA in the institutional databases. Cytologic diagnoses were classified as unsatisfactory, benign, atypical cellular lesion (ACL), follicular neoplasm (FN), suspicious for malignancy, and positive for malignancy. Samples with a histologic discrepancy were re-evaluated, and clinical follow-up information was recorded.
RESULTS: Of 4703 FNA samples, 10.4% were classified as unsatisfactory, 64.6% were classified as benign, 3.2% were classified as ACL, 11.6% were classified as FN, 2.6% were classified as suspicious, and 7.6% were classified as malignant. Five hundred twelve patients had at least 1 repeat FNA, mainly for results in the unsatisfactory and ACL categories. One thousand fifty-two patients had surgical follow-up, including 14.9% of patients with unsatisfactory FNA results, 9.8% of patients with benign results, 40.6% of patients with ACL results, 63.1% of patients with FN results, 86.1% of patients with suspicious results, and 79.3% of patients with malignant results. The rates for histologically confirmed malignancy in these categories were 10.9%, 7.3%, 13.5%, 32.2%, 64.7%, and 98.6%, respectively. The cytologic-histologic diagnostic discrepancy rate was 15.3%. Sources of errors included diagnoses on inadequate specimens, sample errors, and overlapping cytologic features between hyperplastic nodules and follicular adenoma. The sensitivity and specificity of thyroid FNA for the diagnosis of malignancy were 94% and 98.5%, respectively.
CONCLUSIONS: The current results indicated that FNA provides an accurate diagnosis of thyroid malignancy. The 6 diagnostic categories were beneficial for triaging patients for either clinical follow-up or surgical management.

PMID 17680588  Cancer. 2007 Oct 25;111(5):306-15. doi: 10.1002/cncr.22・・・
著者: Mitsuyoshi Hirokawa, J Aidan Carney, John R Goellner, Ronald A DeLellis, Clara S Heffess, Ryohei Katoh, Masahiko Tsujimoto, Kennichi Kakudo
雑誌名: Am J Surg Pathol. 2002 Nov;26(11):1508-14.
Abstract/Text Although histologic definition of follicular thyroid lesions is readily available, application of the diagnostic criteria and personal experience may lead to disagreement among pathologists. To investigate interobserver variation in assessment of encapsulated follicular lesions, eight pathologists (four American and four Japanese) reviewed the same hematoxylin and eosin-stained slide of each of 21 cases of thyroid lesions showing encapsulation and follicular growth pattern. In 10% of the cases, there was complete agreement. At least seven pathologists agreed on the diagnosis in 29% of the cases, and at least six in 76% of the cases. American and Japanese pathologists agreed among themselves in 33% and 52% of cases, respectively. The frequency of diagnosis of adenomatous goiter among Japanese pathologists (31%) was considerably higher than that among American pathologists (6%). In contrast, the frequency of diagnosis (25%) of papillary carcinoma among American pathologists was considerably higher than that (4%) among Japanese pathologists. Our analysis revealed three main factors affecting observer variation: 1) interpretation of the significance of microfollicles intimately related to capillaries within the tumor capsule, 2) evaluation of what constituted the type of nuclear clearing indicative of papillary carcinoma, and 3) absence of clear morphologic criteria for separation of adenomatous goiter and follicular adenoma. To reduce observer variation of encapsulated follicular lesions, it will be necessary to provide more explicit criteria for diagnosis.

PMID 12409728  Am J Surg Pathol. 2002 Nov;26(11):1508-14.
著者: Brigitte Franc, Pauline de la Salmonière, Françoise Lange, Catherine Hoang, Albert Louvel, Anne de Roquancourt, Françoise Vildé, Gilles Hejblum, Sylvie Chevret, Claude Chastang
雑誌名: Hum Pathol. 2003 Nov;34(11):1092-100.
Abstract/Text We evaluated the interobserver and intraobserver reproducibility in the histopathology of follicular thyroid carcinoma (FTC). Forty-one anonymous FTC pathology slides were independently reviewed by 5 pathologists, and 31 of them were also evaluated twice by the same pathologist. A final consensus diagnosis (FCD) was made at the end of the study. Interobserver and intraobserver agreement was determined as the kappa statistic for qualitative data and intraclass correlation coefficient for quantitative data. The agreement between the 5 observers' initial diagnosis and the FCD was 0.69, 0.41, 0.35, 0.28 and 0.11, respectively, strongly suggesting a leadership phenomenon. The FCD classified 30 cases as malignant, including 24 cases diagnosed as FTC. There was unanimous agreement about 13 of the 24 FTCs. Diagnostic reproducibility was found to be acceptable for the nonminimally invasive FTC. Diagnostic discrepancies occurred in 57% of the seven cases classified as minimally invasive FTC by the FCD. FCD excluded malignancy in 11 cases including 6 atypical adenomas. Interobserver and intraobserver agreement for FTC diagnosis was 0.23 (standard error [SE], 0.04) and 0.68, respectively. Interobserver and intraobserver agreement for the presence of vascular invasion was 0.20 (SE, 0.04) and 0.51, respectively, contrasting with a moderate to substantial level of agreement when considering the number of vascular invasion. Interobserver and intraobserver agreement for nucleus optical clearing were slight and moderate, respectively. The importance of the study is the confirmation that diagnostic reproducibility of minimally invasive FTC is low and that this has clinical implications, and also implications for the design of studies into the treatment and outcome of FTC.

PMID 14652809  Hum Pathol. 2003 Nov;34(11):1092-100.
著者: Yasuhiro Ito, Tomonori Yabuta, Mitsuyoshi Hirokawa, Mitsuhiro Fukushima, Hiroyuki Inoue, Takashi Uruno, Minoru Kihara, Takuya Higashiyama, Yuuki Takamura, Akihiro Miya, Kaoru Kobayashi, Fumio Matsuzuka, Nobuyuki Amino, Akira Miyauchi
雑誌名: Endocr J. 2008 Oct;55(5):889-94. Epub 2008 Jun 14.
Abstract/Text Among thyroid nodules arising from follicular cells, benign nodular goiter is thought not to metastasize to regional or distant organs. However, we encountered five cases that were pathologically diagnosed as benign nodular goiter but showed metastasis. The prevalence of benign nodular goiter showing metastasis was 0.17% (5 of 2978 patients). On pathology, there were no detectable signs of carcinoma or follicular adenoma lesions. Two patients showed lymph node metastasis that was pathologically confirmed as metastasis of nodular goiter. One was preoperatively and another was postoperatively detected by ultrasonography. These patients also showed distant metastases that could be ablated by radioiodine. One patient preoperatively showed lung metastasis and the remaining two showed lung and bone metastases and bone metastasis postoperatively. Pathological diagnosis of thyroid nodules has limitations, and cases diagnosed as benign nodular goiter should still undergo careful follow-up.

PMID 18552462  Endocr J. 2008 Oct;55(5):889-94. Epub 2008 Jun 14.
著者: Mitsuyoshi Hirokawa, Takumi Kudo, Hisashi Ota, Ayana Suzuki, Kaoru Kobayashi, Akira Miyauchi
雑誌名: Endocr J. 2017 Sep 30;64(9):859-865. doi: 10.1507/endocrj.EJ17-0111. Epub 2017 Jul 8.
Abstract/Text The aims of this report were to clarify the diagnostic significance of ultrasound (US), fine needle aspiration cytology (FNAC), and flow cytometry for primary thyroid lymphoma, and to establish a preoperative diagnostic algorithm of primary thyroid lymphoma. We retrospectively examined US, FNAC, and flow cytometry in 43 patients with benign lymphoproliferative lesions and 32 patients with primary thyroid lymphoma, who underwent US, FNAC, and flow cytometry at Kuma Hospital between May 2012 and December 2015. Primary thyroid lymphomas included 27 mucosa-associated lymphoid tissue lymphomas, 4 diffuse large B-cell lymphomas, and 1 follicular lymphoma. Flow cytometry had the highest specificity (88.4%) and sensitivity (75.0%). The specificity of US was the lowest (32.6%). Both the positive predictive value (90.5%) and negative predictive value (94.7%) were the highest for FNAC. A scoring system was defined as follows: US, low suspicion 0, intermediate suspicion 1, and high suspicion 2; FNAC, benign 0, undetermined 1, malignant 2; and flow cytometry, 0.33< κ/λ ratio <3 0, κ/λ ratio ≤0.33 2, and κ/λ ratio ≥3 2. We propose that a score ≥4 indicates the need for thyroid resection for diagnosing primary thyroid lymphoma. In such a situation, the case of diffuse large B-cell lymphoma, which was aggressive, was not excluded. Approximately one-fifth of mucosa-associated lymphoid tissue lymphomas may be overlooked, but the patients could be followed up with because of an indolent course.

PMID 28690277  Endocr J. 2017 Sep 30;64(9):859-865. doi: 10.1507/endoc・・・
著者: Gregory W Randolph, Dipti Kamani
雑誌名: Surgery. 2006 Mar;139(3):357-62. doi: 10.1016/j.surg.2005.08.009.
Abstract/Text BACKGROUND: Vocal cord paralysis is associated with extrathyroidal invasive malignancy. This study was performed to analyze the presentation of patients with invasive thyroid malignancy and to determine the preoperative symptomatic and radiographic correlates of vocal cord paralysis.
METHODS: In a group of 365 consecutive patients undergoing thyroidectomy, the group of 21 patients with invasive thyroid malignancy was compared with the 344 patients who had benign thyroid disease or noninvasive cancers.
RESULTS: Preoperative recurrent laryngeal nerve paralysis was a robust marker for invasive thyroid malignancy, being present in 70% of patients with invasive disease and only 0.3% of patients with noninvasive disease. Vocal cord paralysis was associated with voice change in only one third of patients. Preoperative computed tomography was read as positive for vocal cord paralysis in only 25% of patients.
CONCLUSIONS: Laryngoscopic examination is essential for the detection of vocal cord paralysis preoperatively. Symptomatic voice assessment and radiographic evaluation are insufficient. Preoperative vocal cord paralysis tracts with invasive disease and facilitates preoperative recognition of disease extent, allowing for appropriate operative planning and central neck clearance at first operation. Because of the prevalence (approximately 6% in our study) of invasive thyroid disease, the importance of preoperative diagnosis of invasive disease in operative planning and patient counseling, and the importance of vocal cord functional analysis in recurrent laryngeal nerve management algorithms for nerves found infiltrated at operation, and laryngoscopic examination is recommended for all patients undergoing thyroid operation.

PMID 16546500  Surgery. 2006 Mar;139(3):357-62. doi: 10.1016/j.surg.20・・・
著者: Chisato Tomoda, Takashi Uruno, Yuuki Takamura, Yasuhiro Ito, Akihiro Miya, Kaoru Kobayashi, Fumio Matsuzuka, Kanji Kuma, Akira Miyauchi
雑誌名: Surg Today. 2005;35(10):819-22. doi: 10.1007/s00595-005-3037-0.
Abstract/Text PURPOSE: To assess the reliability of ultrasonography (US) for detecting tracheal invasion by papillary thyroid cancer (PTC).
METHODS: We reviewed the clinical and surgical data of 509 patients who underwent surgery for primary PTC during 2003, after routine preoperative US.
RESULTS: Ultrasonography showed possible tracheal invasion in 43 of the 509 patients. However, the US findings could not be evaluated in 32 patients because of high tumor calcification, a tumor diameter greater than 4 cm, or tumor extension inferior to the clavicle. We shaved the tracheal wall in 11 patients and resected the tracheal wall in 2 patients. The sensitivity of US for diagnosing of tracheal invasion was 91%, the specificity 93%, the predictive value of a positive test 25%, the predictive value of a negative test 99%, and the accuracy 93%.
CONCLUSION: Ultrasonography is a useful method of screening for tracheal invasion. A negative sonogram is a reliable indicator of the absence of tracheal invasion, except when tumors are highly calcified or extend inferior to the clavicle.

PMID 16175461  Surg Today. 2005;35(10):819-22. doi: 10.1007/s00595-005・・・
著者: K Shimamoto, H Satake, A Sawaki, T Ishigaki, H Funahashi, T Imai
雑誌名: Eur J Radiol. 1998 Nov;29(1):4-10.
Abstract/Text OBJECTIVE: To evaluate the usefulness of ultrasonography including Doppler flow imaging for the preoperative staging of thyroid papillary carcinoma.
MATERIALS AND METHODS: In 77 patients with thyroid papillary carcinoma who underwent total thyroidectomy, the accuracy of ultrasonography in preoperative clinical staging was assessed with use of pathologic examination on the basis of TNM classification by the International Union Against Cancer (UICC).
RESULTS: In 63 (81.8%) cases, T categories were estimated accurately. The sensitivity in depicting tumor extension into the prethyroidal muscle and/or the sternocleidomastoid muscle was 77.8%, whereas the sensitivity for invasion into the trachea and the esophagus was 42.9 and 28.6%, respectively. In 37 (48.1%) cases, N categories were underestimated, and the sensitivity in the detection of regional lymph node metastasis was 36.7%. Doppler flow imaging was performed in 36 patients, and no correlation was found between flow patterns and the presence of local invasion or regional lymph node metastasis.
CONCLUSION: Ultrasonography was useful for preoperative investigation of thyroid papillary carcinoma, but several limitations existed, especially in evaluating extracapsular invasion to deep locations and regional lymph node metastasis.

PMID 9934552  Eur J Radiol. 1998 Nov;29(1):4-10.
著者: Toshihide Wakamatsu, Kenji Tsushima, Masanori Yasuo, Yoshitaka Yamazaki, Sumiko Yoshikawa, Naohiko Koide, Minoru Fujimori, Tomonobu Koizumi
雑誌名: Respiration. 2006;73(5):651-7. doi: 10.1159/000093160. Epub 2006 May 3.
Abstract/Text BACKGROUND: It is important to confirm preoperative tracheobronchial invasion to enable the selection of the most appropriate treatment.
OBJECTIVE: This study was performed to compare the usefulness of computed tomography (CT), magnetic resonance image (MRI) and bronchoscopy by endobronchial ultrasonography (EBUS) for the assessment of invasion of thyroid or esophageal cancer in cases with suspected tracheobronchial invasion.
METHODS: In cases with suspected contact between the tumor and tracheobronchial wall, CT, MRI and EBUS indicated deformity of the tracheobronchial wall due to the adjacent mass. The final diagnosis was based on surgical and histological results, and/or clinical follow-up.
RESULTS: Fifty-four patients were included in this study. Based on the findings of CT, MRI and EBUS, invasion was suspected in 29, 28 and 25 patients, respectively. Seventeen patients did not undergo surgery based on the results of CT, MRI and bronchoscopy with EBUS. Final diagnosis was intact trachea or bronchial adventitia in 26 patients and invasion in 28 patients. The sensitivity and specificity of CT, MRI and EBUS for invasion were 59 and 56, 75 and 73, and 92 and 83%, respectively. The accuracy of EBUS was significantly greater than that of CT in the present study (p = 0.0011). The accuracy of EBUS was significantly different from that of CT and MRI in the surgically treated patients (p = 0.005 and p = 0.032, respectively).
CONCLUSION: EBUS is the most useful technique for determining the depth and extent of tumor invasion into the airway wall. The combination of MRI and EBUS will contribute to surgical planning in patients with esophageal and thyroid cancer.

PMID 16675895  Respiration. 2006;73(5):651-7. doi: 10.1159/000093160. ・・・
著者: S Takashima, F Takayama, Q Wang, S Kawakami, A Saito, S Kobayashi, S Sone
雑誌名: Acta Radiol. 2000 Jul;41(4):377-83.
Abstract/Text PURPOSE: To assess diagnostic accuracy for tumor invasion of surrounding organs by measurement of tumor circumferences on MR images in patients with differentiated thyroid carcinomas.
MATERIAL AND METHODS: Surgical and MR imaging findings in 50 patients with differentiated thyroid carcinoma (43 primary, 7 recurrent lesions) were retrospectively reviewed. The degrees of circumference of tumor encroachment to the organs were measured, and the measurements and morphologic diagnosis of tumor invasion made by a head and neck radiologist were compared with surgical and pathologic findings using receiver operating characteristic curves.
RESULTS: Diagnosis of tumor invasion by the radiologist was superior to the measurements of the carotid artery and cartilage, while the reverse was true for the trachea and esophagus. However, no statistical differences were noted between them for each structure. Optimal thresholds for tumor invasion were 90 degrees or more for the cartilage (94% accuracy) and esophagus (86% accuracy), 135 degrees or more for the trachea (86% accuracy), and 225 degrees or more for the carotid artery (90% accuracy).
CONCLUSION: Tumor invasion was more accurately diagnosed by measurement of tumor circumferences of each organ on MR images.

PMID 10937763  Acta Radiol. 2000 Jul;41(4):377-83.
著者: 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
雑誌名: 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  Thyroid. 2016 Jan;26(1):1-133. doi: 10.1089/thy.2015.00・・・
著者: Yasuhiro Ito, Akira Miyauchi, Tomoo Jikuzono, Takuya Higashiyama, Yuuki Takamura, Akihiro Miya, Kaoru Kobayashi, Fumio Matsuzuka, Kiyoshi Ichihara, Kanji Kuma
雑誌名: World J Surg. 2007 Apr;31(4):838-48. doi: 10.1007/s00268-006-0455-0.
Abstract/Text BACKGROUND: In 2002, the UICC/AJCC TNM classification for papillary thyroid carcinoma was revised. In this study, we examined the validity of this classification system by investigating the predictors of disease-free survival (DFS) and cause-specific survival (CSS) in patients.
METHODS: We examined various clinicopathological features, including the component of the TNM classification, for 1,740 patients who underwent initial and curative surgery for papillary carcinoma between 1987 and 1995.
RESULTS: Clinical and pathological T4a, clinical N1b in the TNM classification, and patient age were recognized as independent predictors of not only DFS, but also CSS of patients. Tumor size, male gender, and central node metastasis independently affected DFS only. There were 1,005 pathological N1b patients, but pathological N1b did not independently affect either DFS or CSS. Regarding the stage grouping, clinical stage IVA including clinical N1b more clearly affected DFS and CSS than pathological stage IVA including pathological N1b.
CONCLUSION: Clinical stage grouping was more useful than pathological stage grouping for predicting the prognosis of papillary carcinoma patients possibly because pathological stage overestimates the biological characteristics of many pathological N1b tumors.

PMID 17347900  World J Surg. 2007 Apr;31(4):838-48. doi: 10.1007/s0026・・・
著者: Brian Hung-Hin Lang, Chung-Yau Lo, Wai-Fan Chan, King-Yin Lam, Koon-Yat Wan
雑誌名: Ann Surg. 2007 Mar;245(3):366-78. doi: 10.1097/01.sla.0000250445.92336.2a.
Abstract/Text OBJECTIVE: To find out the most predictive staging system for papillary thyroid carcinoma (PTC) currently available in the literature.
BACKGROUND: Various staging systems or risk group stratifications have been used extensively in the clinical management of patients with PTC, but the most predictive system for cancer-specific survival (CSS) based on distinct histologic types remains unclear.
METHODS: Through a comprehensive MEDLINE search from 1965 to 2005, a total of 17 staging systems were found in the literature and 14 systems were applied to the 589 PTC patients managed at our institution from 1961 to 2001. CSS were calculated by Kaplan-Meier method and were compared by log-rank test. Using Cox proportional hazards analysis, the relative importance of each staging system in determining CSS was calculated by the proportion of variation (PVE).
RESULTS: All 14 staging systems significantly predicted CSS (P < 0.001). The 3 highest ranked staging systems by PVE were the Metastases, Age, Completeness of Resection, Invasion, Size (MACIS) (18.7) followed by the new AJCC/UICC 6th edition tumor, node, metastases (TNM) (17.9), and the European Organization for Research and Treatment of Cancer (EORTC) (16.6).
CONCLUSIONS: All of the currently available staging systems predicted CSS well in patients with PTC regardless of which histologic type from which they were derived. When predictability was measured by PVE, the MACIS system was the most predictive staging system and so should be the staging system of choice for PTC in the future.

PMID 17435543  Ann Surg. 2007 Mar;245(3):366-78. doi: 10.1097/01.sla.0・・・
著者: Nobuyuki Wada, Hirotaka Nakayama, Nobuyasu Suganuma, Yoshihiko Masudo, Yasushi Rino, Munetaka Masuda, Toshio Imada
雑誌名: J Clin Endocrinol Metab. 2007 Jan;92(1):215-8. doi: 10.1210/jc.2006-1443. Epub 2006 Oct 31.
Abstract/Text CONTEXT: The prognostic value of the sixth edition AJCC/UICC TNM classification is currently unclear.
OBJECTIVE: The aim was to evaluate the prognostic value of the sixth edition.
DESIGN AND PATIENTS: We retrospectively assessed 354 primary differentiated thyroid carcinomas (77 men and 277 women; age, 51.2 yr; follow-up, 107.6 months) between 1964 and 2003. Sixty percent of patients underwent lobectomy, 40% underwent subtotal/total thyroidectomy, and only 2% were given radioiodine. There were 153, 104, 86, and 11 patients in fifth stages I, II, III, and IV, and 175, 76, 14, 68, 10, and 11 patients in sixth stages I, II, III, IVA, IVB, and IVC, respectively.
RESULTS: New T1-3 had no significant influence. In Cox proportional hazard analysis, T4a and T4b were significantly related to disease-specific survival (DSS). We separately analyzed 68 patients (age 45 yr or older) with extrathyroid extension. These T4 (fifth) tumors were reclassified as 6 T3, 52 T4a, and 10 T4b tumors. The 10-yr DSS rates were 100, 69.3, and 10.0% for T3, T4a, and T4b, respectively. T4b exhibited worse prognoses compared with T4a (P < 0.0001; hazard ratio, 10.1; 95% confidence interval, 4.1-25.3). Stages I and II in both editions achieved favorable prognoses. The 10-yr DSS rates were 67.0 and 27.3% in fifth stages III and IV, and 100, 74.5, 10.0, and 27.3% in sixth stages III, IVA, IVB, and IVC, respectively. DSS curves differed significantly between all sixth TNM stages (P < 0.0001).
CONCLUSION: The sixth edition more accurately predicts different outcomes according to the revised criteria for the degree of extrathyroid extension.

PMID 17077130  J Clin Endocrinol Metab. 2007 Jan;92(1):215-8. doi: 10.・・・
著者: Brian Lang, Chung-Yau Lo, Wai-Fan Chan, King-Yin Lam, Koon-Yat Wan
雑誌名: Ann Surg Oncol. 2007 May;14(5):1551-9. doi: 10.1245/s10434-006-9242-2. Epub 2007 Feb 21.
Abstract/Text BACKGROUND: The AJCC/UICC TNM staging system (TNM) is a widely accepted system for differentiated thyroid carcinoma (DTC). The objective of the present study was to evaluate the potential changes in cancer-specific survival (CSS) after reclassification from fifth to sixth edition TNM.
METHODS: A total of 760 DTC patients managed at our institution from 1961 to 2001 were retrospectively restaged from the fifth to sixth edition TNM. CSS were calculated using Kaplan-Meier method and were compared by the log-rank test. The relative ability of each edition in predicting CSS was calculated by the proportion of variance explained (PVE).
RESULTS: Upon reclassification, the proportion of T1 and T3 tumors increased from 14.2 to 33.4% and 10.0 to 33.7%; T2 and T4 decreased from 44.2 to 25.0% and 31.6 to 7.9%, respectively; N0 remained unchanged at 66.0%; N1a decreased from 25.7 to 4.7%; N1b increased from 8.4 to 29.3%; stages I and IV tumors increased from 55.7 to 60.3% and 3.4 to 17.6%, respectively; stages II and III tumors decreased from 20.5 to 13.9% and 20.4 to 8.2%, respectively. The sixth edition had a higher PVE value than the fifth edition. Significant differences in CSS were observed between stage III (fifth edition) and stage III (sixth edition) and between stage IV (fifth edition) and stage IVA (sixth edition).
CONCLUSIONS: The sixth edition TNM caused marked changes in the pT, pN and allocation of patients into different tumor stages. It appeared to have superior predictability over the fifth edition.

PMID 17318278  Ann Surg Oncol. 2007 May;14(5):1551-9. doi: 10.1245/s10・・・
著者: S Noguchi, N Murakami, H Kawamoto
雑誌名: World J Surg. 1994 Jul-Aug;18(4):552-7; discussion 558.
Abstract/Text Between 1965 and 1988 there were 2953 patients with papillary carcinoma treated at Noguchi Thyroid Clinic. Among them 761 patients were excluded because the primary tumor was < 10 mm in maximum diameter, the patient's age was > 80, or the patient underwent noncurative surgery. The remaining 2192 patients, 192 men and 2000 women, were analyzed. The mean follow-up period was 12.5 years. Total thyroidectomy, subtotal thyroidectomy, lobectomy with or without isthmectomy, and less than lobectomy were performed in 2.3%, 40.3%, 44.2%, and 13.2%, respectively. Modified radical neck dissection, partial node excision, and no node excision were performed in 77.8%, 6.4%, and 15.8%, respectively. Men and women were separately analyzed because their risk factors and prognosis were significantly different. Multivariate analysis was carried out according to Cox's regression hazard model. Independently significant factors affecting prognosis in men were aged and gross nodal metastasis; and age, gross nodal metastasis, tumor size, and number of adhered tissues or organs were the factors in women. Based on those risk factors patients were classified into three groups. For men, 65.6% were classified in the excellent group and their 10-year survival was 98.4%; 17.2% were classified as intermediate and 17.2% as poor with survival rates of 90.1% and 74.4%, respectively. For female patients 69.6% were classified in the excellent group, 18.6% in the intermediate group, and 11.9% in the poor group with 10-year survivals of 99.3%, 96.4%, and 88.8%, respectively.

PMID 7725744  World J Surg. 1994 Jul-Aug;18(4):552-7; discussion 558.・・・
著者: Iwao Sugitani, Nobukatsu Kasai, Yoshihide Fujimoto, Akio Yanagisawa
雑誌名: 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  Surgery. 2004 Feb;135(2):139-48. doi: 10.1016/S0039.
著者: Yasuhiro Ito, Kiyoshi Ichihara, Hiroo Masuoka, Mitsuhiro Fukushima, Hiroyuki Inoue, Minoru Kihara, Chisato Tomoda, Takuya Higashiyama, Yuuki Takamura, Kaoru Kobayashi, Akihiro Miya, Akira Miyauchi
雑誌名: 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  World J Surg. 2010 Nov;34(11):2570-80. doi: 10.1007/s00・・・
著者: Akira Miyauchi, Takumi Kudo, Akihiro Miya, Kaoru Kobayashi, Yasuhiro Ito, Yuuki Takamura, Takuya Higashiyama, Mitsuhiro Fukushima, Minoru Kihara, Hiroyuki Inoue, Chisato Tomoda, Tomonori Yabuta, Hiroo Masuoka
雑誌名: Thyroid. 2011 Jul;21(7):707-16. doi: 10.1089/thy.2010.0355. Epub 2011 Jun 7.
Abstract/Text BACKGROUND: Detectable serum thyroglobulin (Tg) in patients with papillary thyroid carcinoma (PTC) after total thyroidectomy implies unsuccessful surgery, indicating a high risk of recurrence. Serum Tg kinetics in such patients have not been extensively studied. We studied serum Tg kinetics in patients with suppressed serum thyrotropin levels and undetectable anti-Tg antibody to minimize the effects of these factors on Tg values, and evaluated the relationship of prognosis to the serum Tg doubling-time.
METHODS: Between January 1998 and December 2004, 1515 patients with PTC underwent total thyroidectomy in Kuma Hospital. After excluding patients with other thyroid cancers and those positive tests for anti-Tg antibody, there were 426 patients with 4 or more serum Tg measurements at a time that serum thyrotropin concentrations were <0.1 mIU/L. These patients were selected for the present retrospective study. Tg doubling-time was computed using Tg values measured during routine follow-up. Patients were followed for a mean of 88.1 months and a median of 86.7 months.
RESULTS: Of the 426 patients, 137 patients had 4 or more measurements that revealed detectable Tg in serum Tg. The Tg doubling-time (DT), calculated using all available data, varied widely, and were grouped into those that were <1 year (17 patients), those that were 1-3 years (21 patients), and those that were ≥ 3 years (30 patients), as well as those with a negative value due to decrease in serum Tg (69 patients). There were also 88 patients who had three or fewer serum Tg measurements that showed detectable Tg levels, as well as 201 patients in whom serum Tg measurements were below the lower limit of detection. In the group of patients with a Tg-DT of <1 year the cause specific survival at 10 years was 50%, and in the group with a Tg-DT of 1-3 years it was 95%. In all other groups it was 100%. Many classical prognostic factors (TNM stage, age, and gender) as well as the Tg-DT were significant indicators of survival by univariate analysis, but Tg-DT remained the only independent predictor by multivariate analysis. Tg-DT was also the only independent predictor of distant metastases and loco-regional recurrence on multivariate analysis. Tg-DT calculated using only the first four data [Tg-DT (first four data)] was also the only independent predictor of survival, distant metastases, and loco-regional recurrence on multivariate analysis.
CONCLUSIONS: Tg-DT (all data or first four data) is a very strong prognostic predictor superior to the classical prognostic factors in patients with PTC.

PMID 21649472  Thyroid. 2011 Jul;21(7):707-16. doi: 10.1089/thy.2010.0・・・
著者: Won Gu Kim, Jong Ho Yoon, Won Bae Kim, Tae Yong Kim, Eui Young Kim, Jung Min Kim, Jin-Sook Ryu, Gyungyub Gong, Suck Joon Hong, Young Kee Shong
雑誌名: J Clin Endocrinol Metab. 2008 Dec;93(12):4683-9. doi: 10.1210/jc.2008-0962. Epub 2008 Sep 23.
Abstract/Text OBJECTIVES: The aim of the study was to evaluate the usefulness of the antithyroglobulin autoantibody (TgAb) value at 6-12 months after remnant ablation in predicting recurrence in differentiated thyroid carcinoma patients who had undetectable thyroglobulin (Tg) values. The change in TgAb concentration measured between the time of remnant ablation (TgAb1) and 6-12 months thereafter (TgAb2) was also evaluated as a possible prognostic indicator.
PATIENTS AND METHODS: Patients with differentiated thyroid carcinoma who underwent total thyroidectomy followed by (131)I remnant ablation between 1995 and 2003 at the Asan Medical Center (Seoul, Korea) were enrolled. Of these, 824 patients with undetectable Tg at 6-12 months after remnant ablation during thyroid hormone withdrawal were the subjects of this study.
RESULTS: TgAb2 was positive in 56 patients. Ten of 56 patients (18%) with positive TgAb2 had recurrence, whereas only 10 of 768 patients (1%) with negative TgAb2 had recurrence during 73.6 months of follow-up (P < 0.001). The change between TgAb1 and TgAb2 levels was evaluated in patients with positive TgAb2. TgAb concentration decreased by more than 50% in 21 patients (group 1) and by less than 50% in 16 patients (group 2), and it increased in 19 patients (group 3). The recurrence rates in groups 1, 2, and 3 were 0, 19, and 37%, respectively (P = 0.016).
CONCLUSIONS: Serum TgAb levels measured at 6-12 months after remnant ablation could predict recurrence in patients with undetectable Tg values. In patients with undetectable Tg and positive TgAb values, a change in TgAb concentration during the early postoperative period may be a prognostic indicator of recurrence.

PMID 18812478  J Clin Endocrinol Metab. 2008 Dec;93(12):4683-9. doi: 1・・・
著者: R Michael Tuttle, Hernan Tala, Jatin Shah, Rebecca Leboeuf, Ronald Ghossein, Mithat Gonen, Matvey Brokhin, Gal Omry, James A Fagin, Ashok Shaha
雑誌名: Thyroid. 2010 Dec;20(12):1341-9. doi: 10.1089/thy.2010.0178. Epub 2010 Oct 29.
Abstract/Text BACKGROUND: A risk-adapted approach to management of thyroid cancer requires risk estimates that change over time based on response to therapy and the course of the disease. The objective of this study was to validate the American Thyroid Association (ATA) risk of recurrence staging system and determine if an assessment of response to therapy during the first 2 years of follow-up can modify these initial risk estimates.
METHODS: This retrospective review identified 588 adult follicular cell-derived thyroid cancer patients followed for a median of 7 years (range 1-15 years) after total thyroidectomy and radioactive iodine remnant ablation. Patients were stratified according to ATA risk categories (low, intermediate, or high) as part of initial staging. Clinical data obtained during the first 2 years of follow-up (suppressed thyroglobulin [Tg], stimulated Tg, and imaging studies) were used to re-stage each patient based on response to initial therapy (excellent, acceptable, or incomplete). Clinical outcomes predicted by initial ATA risk categories were compared with revised risk estimates obtained after response to therapy variables were used to modify the initial ATA risk estimates.
RESULTS: Persistent structural disease or recurrence was identified in 3% of the low-risk, 21% of the intermediate-risk, and 68% of the high-risk patients (p < 0.001). Re-stratification during the first 2 years of follow-up reduced the likelihood of finding persistent structural disease or recurrence to 2% in low-risk, 2% in intermediate-risk, and 14% in high-risk patients, demonstrating an excellent response to therapy (stimulated Tg < 1 ng/mL without structural evidence of disease). Conversely, an incomplete response to initial therapy (suppressed Tg > 1 ng/mL, stimulated Tg > 10 ng/mL, rising Tg values, or structural disease identification within the first 2 years of follow-up) increased the likelihood of persistent structural disease or recurrence to 13% in low-risk, 41% in intermediate-risk, and 79% in high-risk patients.
CONCLUSIONS: Our data confirm that the newly proposed ATA recurrence staging system effectively predicts the risk of recurrence and persistent disease. Further, these initial ATA risk estimates can be significantly refined based on the assessment of response to initial therapy, thereby providing a dynamic risk assessment that can be used to more effectively tailor ongoing follow-up recommendations.

PMID 21034228  Thyroid. 2010 Dec;20(12):1341-9. doi: 10.1089/thy.2010.・・・
著者: Maria Grazia Castagna, Fabio Maino, Claudia Cipri, Valentina Belardini, Alexandra Theodoropoulou, Gabriele Cevenini, Furio Pacini
雑誌名: Eur J Endocrinol. 2011 Sep;165(3):441-6. doi: 10.1530/EJE-11-0466. Epub 2011 Jul 12.
Abstract/Text INTRODUCTION: After initial treatment, differentiated thyroid cancer (DTC) patients are stratified as low and high risk based on clinical/pathological features. Recently, a risk stratification based on additional clinical data accumulated during follow-up has been proposed.
OBJECTIVE: To evaluate the predictive value of delayed risk stratification (DRS) obtained at the time of the first diagnostic control (8-12 months after initial treatment).
METHODS: We reviewed 512 patients with DTC whose risk assessment was initially defined according to the American (ATA) and European Thyroid Association (ETA) guidelines. At the time of the first control, 8-12 months after initial treatment, patients were re-stratified according to their clinical status: DRS.
RESULTS: Using DRS, about 50% of ATA/ETA intermediate/high-risk patients moved to DRS low-risk category, while about 10% of ATA/ETA low-risk patients moved to DRS high-risk category. The ability of the DRS to predict the final outcome was superior to that of ATA and ETA. Positive and negative predictive values for both ATA (39.2 and 90.6% respectively) and ETA (38.4 and 91.3% respectively) were significantly lower than that observed with the DRS (72.8 and 96.3% respectively, P<0.05). The observed variance in predicting final outcome was 25.4% for ATA, 19.1% for ETA, and 62.1% for DRS.
CONCLUSIONS: Delaying the risk stratification of DTC patients at a time when the response to surgery and radioiodine ablation is evident allows to better define individual risk and to better modulate the subsequent follow-up.

PMID 21750043  Eur J Endocrinol. 2011 Sep;165(3):441-6. doi: 10.1530/E・・・
著者: L J DeGroot, E L Kaplan, M McCormick, F H Straus
雑誌名: J Clin Endocrinol Metab. 1990 Aug;71(2):414-24. doi: 10.1210/jcem-71-2-414.
Abstract/Text We have analyzed the course of papillary thyroid carcinoma in 269 patients managed at the University of Chicago, with an average follow-up period of 12 yr from the time of diagnosis. Patients were categorized by clinical class; I, with intrathyroidal disease; II, with cervical nodal metastases; III, with extrathyroidal invasion; and IV, with distant metastases. Half of the patients had a history of thyroid enlargement known, on the average, for over 3 yr. In 15% of patients given thyroid hormone, the mass decreased in size. The peak incidence of cancer was when subjects were between 20-40 yr of age. Tumors averaged 2.4 cm in size; 21.6% had tumor capsule invasion, and 46% of patients had multifocal tumors. Sixty-six percent of the patients had near-total or total thyroidectomy. The overall incidence of postoperative hypoparathyroidism was 8.4%, but the incidence was zero in 83 near-total or total thyroidectomies carried out by 1 surgeon. Twenty-five percent of the patients had continuing or recurrent disease, and 8.2% died from cancer. Deaths occurred largely in patients with class III or IV disease. Cervical lymph nodes were associated with increased recurrences, but not increased deaths. Extrathyroidal invasion carried an increased risk of 5.8-fold for death, and distant metastases increased this risk 47-fold. Age over 45 yr at diagnosis increased the risk of death 32-fold. Tumor size over 3 cm increased the risk of death 5.8-fold. Surgical treatment combining lobectomy plus at least contralateral subtotal thyroidectomy was associated, by Cox proportional hazard analysis, with decreased risk of death in patients with tumors larger than 1 cm and decreased risk of recurrence among all patients, including patients in classes I and II, compared to patients who underwent unilateral thyroid surgery or bilateral subtotal resections. By chi 2 analysis, 131I ablation of residual thyroid tissue after operation was associated with decreased risk of recurrence in tumors larger than 1 cm and decreased risk of death in patients in classes I and II with tumors more than 1 cm in size. The data strongly support the use of more extensive initial surgery in class I and II patients with tumors more than 1 cm in size as well as postoperative radioactive 131I ablation of thyroid remnant tissue.

PMID 2380337  J Clin Endocrinol Metab. 1990 Aug;71(2):414-24. doi: 10・・・
著者: N A Samaan, P N Schultz, R C Hickey, H Goepfert, T P Haynie, D A Johnston, N G Ordonez
雑誌名: J Clin Endocrinol Metab. 1992 Sep;75(3):714-20. doi: 10.1210/jcem.75.3.1517360.
Abstract/Text This study analyzed the impact of prognostic variables of age, sex, histopathological diagnosis, extent of disease at diagnosis, and surgical intervention on well differentiated thyroid carcinoma and how surgical treatment, radioactive iodine, and radiotherapy influence the patients' outcomes. There have been 1599 patients with well differentiated thyroid cancer treated and followed at the University of Texas M.D. Anderson Cancer Center from 1948 to 1989. The median follow-up for all patients was 11.0 yr, with the maximum follow-up being 43 yr and the minimum follow-up being 1 yr. The patients were predominantly female (2.3:1), with papillary (81%) and intrathyroidal carcinomas (42%) at the time of diagnosis. Sixty-six percent of the patients had a total thyroidectomy, 7% received external radiotherapy, and 46% had radioactive iodine as part of the treatment of the original disease; the overall recurrence rate was 23%, and the death rate was 11%. This study showed that treatment with radioactive iodine was the single most powerful prognostic indicator for increased disease-free interval (P less than 0.001) and that its use significantly increased survival as well. No benefit was obtained from treatment with external radiotherapy. Children had the best overall survival, but of the adult patients, females who had intrathyroidal papillary disease treated with total thyroidectomy, who had been given radioactive iodine, and whose disease had been diagnosed between 20-59 yr of age had the best prognosis.

PMID 1517360  J Clin Endocrinol Metab. 1992 Sep;75(3):714-20. doi: 10・・・
著者: Ian D Hay, Geoffrey B Thompson, Clive S Grant, Eric J Bergstralh, Catherine E Dvorak, Colum A Gorman, Megan S Maurer, Bryan McIver, Brian P Mullan, Ann L Oberg, Claudia C Powell, Jon A van Heerden, John R Goellner
雑誌名: World J Surg. 2002 Aug;26(8):879-85. doi: 10.1007/s00268-002-6612-1. Epub 2002 May 21.
Abstract/Text It is uncertain whether more extensive primary surgery and increasing use of radioiodine remnant ablation (RRA) for papillary thyroid carcinoma (PTC) have resulted in improved rates of cause-specific mortality (CSM) and tumor recurrence (TR). Details of the initial presentation, therapy, and outcome of 2444 PTC patients consecutively treated during 1940-1999 were recorded in a computerized database. Patients were followed for more than 43,000 patient-years. The 25-year rates for CSM and TR were 5% and 14%, respectively. Temporal trends were analyzed for six decades. During the six decades, the proportion with initial MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) scores <6 were 77%, 82%, 84%, 86%, 85%, and 82%, respectively (p = 0.06). Lobectomy accounted for 70% of initial procedures during 1940-1949 and 22% during 1950-1959; during 1960-1999 bilateral lobar resection (BLR) accounted for 91% of surgeries (p <0.001). RRA after BLR was performed during 1950-1969 in 3% but increased to 18%, 57%, and 46% in successive decades (p <0.001). The 40-year rates for CSM and TR during 1940-1949 were significantly higher (p = 0.002) than during 1950-1999. During the last 50 years the 10-year CSM and TR rates for the 2286 cases did not significantly change with successive decades. Moreover, the 10-year rates for CSM and TR were not significantly improved during the last five decades of the study, either for the 1917 MACIS <6 patients or the 369 MACIS < 6 patients. Increasing use of RRA has not apparently improved the already excellent outcome, achieved before 1970, in low risk (MACIS <6) PTC patients managed by near-total thyroidectomy and conservative nodal excision.

PMID 12016468  World J Surg. 2002 Aug;26(8):879-85. doi: 10.1007/s0026・・・
著者: L E Sanders, B Cady
雑誌名: Arch Surg. 1998 Apr;133(4):419-25.
Abstract/Text OBJECTIVE: To reexamine the age, metastases, extent, and size (AMES) risk criteria for well-differentiated thyroid cancer with the effect of therapy on outcome.
DESIGN: Review of patient medical records and direct-contact follow-up.
SETTING: Two tertiary referral centers.
MAIN OUTCOME MEASURES: Recurrence or death.
PATIENTS: One thousand nineteen patients with well-differentiated thyroid cancer treated between 1940 and 1990.
RESULTS: One thousand nineteen patients with well-differentiated thyroid cancer were treated between 1940 and 1990, with a mean follow-up of 13 years, including a recent group of 264 patients treated from 1980 to 1990 at 2 different institutions with a mean follow-up of 8 years. The AMES criteria were used to designate high- and low-risk patients. The entire group had 229 high- and 790 low-risk patients; the percentage of high-risk patients decreased slightly after 1960. From 1940 to 1960, 1960 to 1979, and 1980 to 1990, the high-risk groups had survival rates of 48%, 62%, and 47%, respectively. For the low-risk patients, survival rates were 96%, 98%, and 98%, respectively. Recurrences occurred in 5% of low-risk patients and were usually curable; in high-risk patients, recurrence was associated with a 75% mortality. In low-risk patients, there was no significant difference in recurrence or death according to type of operation (unilateral or bilateral) or use of radioactive iodine. In high-risk patients, there were trends toward but no significant improvement in survival with bilateral surgery and radioactive iodine therapy; thyroid replacement was associated with a significant improvement in survival.
CONCLUSIONS: The AMES risk criteria remain highly valid predictors of risk. They define most low-risk patients for whom radical treatment may add excess morbidity but not improve already excellent prognoses.

PMID 9565123  Arch Surg. 1998 Apr;133(4):419-25.
著者: E L Mazzaferri
雑誌名: Thyroid. 1997 Apr;7(2):265-71.
Abstract/Text Outcome was compared in 1,004 patients with differentiated thyroid carcinoma (DTC) who underwent thyroid remnant ablation with 131I (n = 151) or were either treated with thyroid hormone alone (755) or given no postoperative medical therapy (98). Median follow-up time was 18.7 years for patients treated with thyroid hormone alone, 21.3 years for those given no adjunctive medical therapy, and 14.7 years for those treated with thyroid remnant ablation. End points measured were cancer recurrence, development of distant metastases, and death due to thyroid carcinoma. Tumor recurrence was about threefold lower (p < 0.001) and fewer patients developed distant metastases (p < 0.002) after thyroid remnant ablation than after other forms of postoperative treatment, an effect observed only in patients with primary tumors > or = 1.5 cm in diameter. The doses of 131I were stratified into two groups: 29-50 mCi (mean 47 mCi) in 43% and 51-200 mCi (111 mCi) in 57% of patients. Both groups experienced similar recurrence rates (7% and 9%, respectively, p = 0.7). There were fewer cancer deaths after thyroid remnant ablation than after the other treatment strategies (p < 0.001), differences that occurred only in patients aged 40 years or older at the time of initial treatment and with primary tumors > or = 1.5 cm. The variables that influenced cancer recurrence in a Cox proportional hazards model were absence of cervical lymph node metastases (hazards ratio [HR] 0.8), tumor stage (HR 1.8), and treatment of the thyroid remnant (HR 0.9); those that independently affected cancer-specific death rates were age (HR 13.3), recurrence of cancer (16.6), time to treatment (HR 3.5), thyroid remnant ablation (HR 0.5), and tumor stage (HR 2.3). This study suggests that thyroid remnant ablation is effective in reducing recurrence of DTC in patients of all ages and reduces the risk of death from thyroid carcinoma in patients > age 40 at the time of diagnosis. These effects are not apparent in patients with isolated tumors < 1.5 cm that are not metastatic to regional lymph nodes or invading the thyroid capsule. The optimal dose of 131I necessary to achieve this effect remains uncertain.

PMID 9133698  Thyroid. 1997 Apr;7(2):265-71.
著者: G Brabant
雑誌名: J Clin Endocrinol Metab. 2008 Apr;93(4):1167-9. doi: 10.1210/jc.2007-2228.
Abstract/Text
PMID 18390811  J Clin Endocrinol Metab. 2008 Apr;93(4):1167-9. doi: 10・・・
著者: D S Cooper, B Specker, M Ho, M Sperling, P W Ladenson, D S Ross, K B Ain, S T Bigos, J D Brierley, B R Haugen, I Klein, J Robbins, S I Sherman, T Taylor, H R Maxon
雑誌名: Thyroid. 1998 Sep;8(9):737-44.
Abstract/Text The ideal therapy for differentiated thyroid cancer is uncertain. Although thyroid hormone treatment is pivotal, the degree of thyrotropin (TSH) suppression that is required to prevent recurrences has not been studied in detail. We have examined the relation of TSH suppression to baseline disease characteristics and to the likelihood of disease progression in a cohort of thyroid cancer patients who have been followed in a multicenter thyroid cancer registry that was established in 1986. The present study describes 617 patients with papillary and 66 patients with follicular thyroid cancer followed annually for a median of 4.5 years (range 1-8.6 years). Cancer staging was assessed using a staging scheme developed and validated by the registry. Cancer status was defined as no residual disease; progressive disease at any follow-up time; or death from thyroid cancer. A mean TSH score was calculated for each patient by averaging all available TSH determinations, where 1 = undetectable TSH; 2 = subnormal TSH; 3 = normal TSH; and 4 = elevated TSH. Patients were also grouped by their TSH scores: group 1: mean TSH score 1.0-1.99; group 2: mean TSH score 2.0-2.99; group 3: mean TSH score 3.0-4.0. The degree of TSH suppression did not differ between papillary and follicular thyroid cancer patients. However, TSH suppression was greater in papillary cancer patients who were initially classified as being at higher risk for recurrence. This was not the case for follicular cancer patients, where TSH suppression was similar for all patients. For all stages of papillary cancer, a Cox proportional hazards model showed that disease stage, patient age, and radioiodine therapy all predicted disease progression, but TSH score category did not. However, TSH score category was an independent predictor of disease progression in high risk patients (p = 0.03), but was no longer significant when radioiodine therapy was included in the model (p = 0.09). There were too few patients with follicular cancer for multivariate analysis. These data suggest that physicians use greater degrees of TSH suppression in higher risk papillary cancer patients. Our data do not support the concept that greater degrees of TSH suppression are required to prevent disease progression in low-risk patients, but this possibility remains in high-risk patients. Additional studies with more patients and longer follow-up may provide the answer to this important question.

PMID 9777742  Thyroid. 1998 Sep;8(9):737-44.
著者: Jacqueline Jonklaas, Nicholas J Sarlis, Danielle Litofsky, Kenneth B Ain, S Thomas Bigos, James D Brierley, David S Cooper, Bryan R Haugen, Paul W Ladenson, James Magner, Jacob Robbins, Douglas S Ross, Monica Skarulis, Harry R Maxon, Steven I Sherman
雑誌名: Thyroid. 2006 Dec;16(12):1229-42. doi: 10.1089/thy.2006.16.1229.
Abstract/Text This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid cancer patients. The study setting was a prospectively followed multi-institutional registry. Patients were stratified as low risk (stages I and II) or high risk (stages III and IV). Treatments employed included near-total thyroidectomy, administration of radioactive iodine, and thyroid hormone suppression therapy. Outcome measures were overall survival, disease-specific survival, and disease-free survival. Near-total thyroidectomy, radioactive iodine, and aggressive thyroid hormone suppression therapy were each independently associated with longer overall survival in high-risk patients. Near-total thyroidectomy followed by radioactive iodine therapy, and moderate thyroid hormone suppression therapy, both predicted improved overall survival in stage II patients. No treatment modality, including lack of radioactive iodine, was associated with altered survival in stage I patients. Based on our overall survival data, we confirm that near-total thyroidectomy is indicated in high-risk patients. We also conclude that radioactive iodine therapy is beneficial for stage II, III, and IV patients. Importantly, we show for the first time that superior outcomes are associated with aggressive thyroid hormone suppression therapy in high-risk patients, but are achieved with modest suppression in stage II patients. We were unable to show any impact, positive or negative, of specific therapies in stage I patients.

PMID 17199433  Thyroid. 2006 Dec;16(12):1229-42. doi: 10.1089/thy.2006・・・
著者: Nayahmka J McGriff, Gyorgy Csako, Loukas Gourgiotis, Guthrie Lori C, Frank Pucino, Nicholas J Sarlis
雑誌名: Ann Med. 2002;34(7-8):554-64.
Abstract/Text BACKGROUND: Long-term thyroid hormone (TH) therapy aiming at the suppression of serum thyrotropin (TSH) has been traditionally used in the management of well differentiated thyroid cancer (ThyrCa). However, formal validation of the effects of thyroid hormone suppression therapy (THST) through randomized controlled trials is lacking. Additionally, the role - if any - of TSH effect at low ambient concentrations upon human thyroid tumorigenesis remains unclear.
AIM: Evaluation of the effect of THST on the clinical outcomes of papillary and/or follicular ThyrCa.
METHODS: By using a quantitative research synthesis approach in a cumulative ThyrCa cohort, we evaluated the effect of THST on the likelihood of major adverse clinical events (disease progression/recurrence and death). A total of 28 clinical trials published during the period 1934-2001 were identified; only 10 were amenable to meta-analysis. Causality was assessed by Hill criteria.
RESULTS: Out of 4, 174 patients with ThyrCa, 2, 880 (69%) were reported as being on THST. Meta-analysis showed that the group of patients who received THST had a decreased risk of major adverse clinical events (RR = 0.73; Cl = 0.60-0.88; P < 0.05). Further, by applying a Likert scale, 15/17 interpretable studies showed either a 'likely' or 'questionable' beneficial effect of THST. Assessment of causality between TSHT and reduction of major adverse clinical events suggested a probable association.
CONCLUSIONS: THST appears justified in ThyrCa patients following initial therapy. As most primary studies were imperfect, future research will better define the effect of THST upon ThyrCa clinical outcomes.

PMID 12553495  Ann Med. 2002;34(7-8):554-64.
著者: C T Sawin, A Geller, P A Wolf, A J Belanger, E Baker, P Bacharach, P W Wilson, E J Benjamin, R B D'Agostino
雑誌名: N Engl J Med. 1994 Nov 10;331(19):1249-52. doi: 10.1056/NEJM199411103311901.
Abstract/Text BACKGROUND: Low serum thyrotropin concentrations are a sensitive indicator of hyperthyroidism but can also occur in persons who have no clinical manifestations of the disorder. We studied whether low serum thyrotropin concentrations in clinically euthyroid older persons are a risk factor for subsequent atrial fibrillation.
METHODS: We studied 2007 persons (814 men and 1193 women) 60 years of age or older who did not have atrial fibrillation in order to determine the frequency of this arrhythmia during a 10-year follow-up period. The subjects were classified according to their serum thyrotropin concentrations: those with low values (< or = 0.1 mU per liter; 61 subjects); those with slightly low values (> 0.1 to 0.4 mU per liter; 187 subjects); those with normal values (> 0.4 to 5.0 mU per liter; 1576 subjects); and those with high values (> 5.0 mU per liter; 183 subjects).
RESULTS: During the 10-year follow-up period, atrial fibrillation occurred in 13 persons with low initial values for serum thyrotropin, 23 with slightly low values, 133 with normal values, and 23 with high values. The cumulative incidence of atrial fibrillation at 10 years was 28 percent among the subjects with low serum thyrotropin values (< or = 0.1 mU per liter), as compared with 11 percent among those with normal values; the age-adjusted incidence of atrial fibrillation was 28 per 1000 person-years among those with low values and 10 per 1000 person-years among those with normal values (P = 0.005). After adjustment for other known risk factors, the relative risk of atrial fibrillation in elderly subjects with low serum thyrotropin concentrations, as compared with those with normal concentrations, was 3.1 (95 percent confidence interval, 1.7 to 5.5; P < 0.001). The 10-year incidence of atrial fibrillation in the groups with slightly low and high serum thyrotropin values was not significantly different from that in the group with normal values.
CONCLUSIONS: Among people 60 years of age or older, a low serum thyrotropin concentration is associated with a threefold higher risk that atrial fibrillation will develop in the subsequent decade.

PMID 7935681  N Engl J Med. 1994 Nov 10;331(19):1249-52. doi: 10.1056・・・
著者: A D Toft
雑誌名: N Engl J Med. 2001 Aug 16;345(7):512-6. doi: 10.1056/NEJMcp010145.
Abstract/Text
PMID 11519506  N Engl J Med. 2001 Aug 16;345(7):512-6. doi: 10.1056/NE・・・
著者: P Pujol, J P Daures, N Nsakala, L Baldet, J Bringer, C Jaffiol
雑誌名: J Clin Endocrinol Metab. 1996 Dec;81(12):4318-23. doi: 10.1210/jcem.81.12.8954034.
Abstract/Text We investigate whether the prognosis of patients with differentiated thyroid cancer is improved by maintaining a greater level of TSH suppression. One hundred and forty-one patients who underwent hormone therapy after thyroidectomy were followed up from 1970 to 1993 (mean, 95 months). Patients received levothyroxine (L-T4; mean dose, 2.6 micrograms/kg-day). TSH suppression was evaluated by TRH stimulation test until 1986 and thereafter by a second generation immunoradiometric assay. As TSH underwent fluctuation over time in most patients, we focused on subgroups of patients with relatively constant TSH levels during the follow-up. The relapse-free survival (RFS) was longer in the group with constantly suppressed TSH (all TSH values, < or = 0.05 mU/L; n = 18) than in the group with nonsuppressed TSH (all TSH values, > or = 1 mU/L; n = 15; P < 0.01). Age, sex, tumor node metastasis stage, and initial therapy were not different between the suppressed and nonsuppressed TSH groups. In the overall population, we analyzed the level of TSH suppression by studying the percentage of undetectable TSH values (< or = 0.05 mU/L) during the follow-up. The patients with a greater degree of TSH suppression (> 90% of undetectable TSH values; n = 19) had a trend toward a longer RFS than the remaining population (n = 102; P = 0.14). The patients with a lesser degree of TSH suppression (< 10% of undetectable TSH values; n = 27) had a shorter RFS than the remaining patients (n = 94; P < 0.01). In multivariate analysis that included TSH suppression, age, sex, histology, and tumor node metastasis stage, the degree of TSH suppression predicted RFS independently of other factors (P = 0.02). This study shows that a lesser degree of TSH suppression is associated with an increased incidence of relapse, supporting the hypothesis that a high level of TSH suppression is required for the endocrine management of thyroid cancer.

PMID 8954034  J Clin Endocrinol Metab. 1996 Dec;81(12):4318-23. doi: ・・・
著者: Mitsuru Ito, Akira Miyauchi, Shinji Morita, Takumi Kudo, Eijun Nishihara, Minoru Kihara, Yuuki Takamura, Yasuhiro Ito, Kaoru Kobayashi, Akihiro Miya, Sumihisa Kubota, Nobuyuki Amino
雑誌名: Eur J Endocrinol. 2012 Sep;167(3):373-8. doi: 10.1530/EJE-11-1029. Epub 2012 Jun 18.
Abstract/Text OBJECTIVE: Thyroidal production of triiodothyronine (T(3)) is absent in patients who have undergone total thyroidectomy. Therefore, relative T(3) deficiency may occur during postoperative levothyroxine (L-T(4)) therapy. The objective of this study was to evaluate how the individual serum T(3) level changes between preoperative native thyroid function and postoperative L-T(4) therapy.
METHODS: We retrospectively studied 135 consecutive patients with papillary thyroid carcinoma, who underwent total thyroidectomy. Serum free T(4) (FT(4)), free T(3) (FT(3)), and TSH levels measured preoperatively were compared with those levels measured on postoperative L-T(4) therapy.
RESULTS: serum tsh levels during postoperative L-T(4) therapy were significantly decreased compared with native TSH levels (P<0.001). serum FT(4) levels were significantly increased (P<0.001). Serum FT(3) levels were significantly decreased (P=0.029). We divided the patients into four groups according to postoperative serum TSH levels: strongly suppressed (less than one-tenth of the lower limit); moderately suppressed (between one-tenth of the lower limit and the lower limit); normal limit; and more than upper limit. Patients with strongly suppressed TSH levels had serum FT(3) levels significantly higher than the native levels (P<0.001). Patients with moderately suppressed TSH levels had serum FT(3) levels equivalent to the native levels (P=0.51), and patients with normal TSH levels had significantly lower serum FT(3) levels (P<0.001).
CONCLUSIONS: Serum FT(3) levels during postoperative L-T(4) therapy were equivalent to the preoperative levels in patients with moderately suppressed TSH levels. Our study indicated that a moderately TSH-suppressive dose of L-T(4) is required to achieve the preoperative native serum T(3) levels in postoperative L-T(4) therapy.

PMID 22711760  Eur J Endocrinol. 2012 Sep;167(3):373-8. doi: 10.1530/E・・・
著者: American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, David S Cooper, Gerard M Doherty, Bryan R Haugen, Bryan R Hauger, Richard T Kloos, Stephanie L Lee, Susan J Mandel, Ernest L Mazzaferri, Bryan McIver, Furio Pacini, Martin Schlumberger, Steven I Sherman, David L Steward, R Michael Tuttle
雑誌名: Thyroid. 2009 Nov;19(11):1167-214. doi: 10.1089/thy.2009.0110.
Abstract/Text BACKGROUND: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Association's guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines.
METHODS: Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force.
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, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and serum thyroglobulin as well as those related to management of recurrent and metastatic disease.
CONCLUSIONS: We created evidence-based recommendations in response to our appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

PMID 19860577  Thyroid. 2009 Nov;19(11):1167-214. doi: 10.1089/thy.200・・・
著者: John C Watkinson, British Thyroid Association
雑誌名: Nucl Med Commun. 2004 Sep;25(9):897-900.
Abstract/Text
PMID 15319594  Nucl Med Commun. 2004 Sep;25(9):897-900.
著者: R H Cobin, H Gharib, D A Bergman, O H Clark, D S Cooper, G H Daniels, R A Dickey, D S Duick, J R Garber, I D Hay, J S Kukora, H M Lando, A B Schorr, M A Zeiger, Thyroid Carcinoma Task Force
雑誌名: Endocr Pract. 2001 May-Jun;7(3):202-20.
Abstract/Text
PMID 11430305  Endocr Pract. 2001 May-Jun;7(3):202-20.
著者: F Pacini, P W Ladenson, M Schlumberger, A Driedger, M Luster, R T Kloos, S Sherman, B Haugen, C Corone, E Molinaro, R Elisei, C Ceccarelli, A Pinchera, R L Wahl, S Leboulleux, M Ricard, J Yoo, N L Busaidy, E Delpassand, H Hanscheid, R Felbinger, M Lassmann, C Reiners
雑誌名: J Clin Endocrinol Metab. 2006 Mar;91(3):926-32. doi: 10.1210/jc.2005-1651. Epub 2005 Dec 29.
Abstract/Text CONTEXT: After surgery for differentiated thyroid carcinoma, many patients are treated with radioiodine to ablate remnant thyroid tissue. This procedure has been performed with the patient in the hypothyroid state to promote endogenous TSH stimulation and is often associated with hypothyroid symptoms and impaired quality of life. OBJECTIVE AND INTERVENTION: This international, randomized, controlled, multicenter trial aimed to compare the efficacy and safety of recombinant human TSH (rhTSH) to prepare euthyroid patients on L-thyroxine therapy (euthyroid group) to ablate remnant thyroid tissue with 3.7 GBq (100 mCi) 131I, compared with that with conventional remnant ablation performed in the hypothyroid state (hypothyroid group). Quality of life was determined at the time of randomization and ablation. After the administration of the 131-I dose, the rate of radiation clearance from blood, thyroid remnant, and whole body was measured.
RESULTS: The predefined primary criterion for successful ablation was "no visible uptake in the thyroid bed, or if visible, fractional uptake less than 0.1%" on neck scans performed 8 months after therapy and was satisfied in 100% of patients in both groups. A secondary criterion for ablation, an rhTSH-stimulated serum thyroglobulin concentration less than 2 ng/ml, was fulfilled by 23 of 24 (96%) euthyroid patients and 18 of 21 (86%) hypothyroid patients (P = 0.2341). Quality of life was well preserved in the euthyroid group, compared with the hypothyroid group, as demonstrated by their lower pretreatment scores on the Billewicz scale for hypothyroid signs and symptoms, 27 +/- 7 vs. 18 +/- 4 (P < 0.0001) and their significantly higher Short Form-36 Health Assessment Scale scores in five of eight categories. Euthyroid patients had a statistically significant one third lower radiation dose to the blood, compared with patients in the hypothyroid group.
CONCLUSIONS: This study demonstrates comparable remnant ablation rates in patients prepared for 131I remnant ablation with 3.7 GBq by either administering rhTSH or withholding thyroid hormone. rhTSH-prepared patients maintained a higher quality of life and received less radiation exposure to the blood.

PMID 16384850  J Clin Endocrinol Metab. 2006 Mar;91(3):926-32. doi: 10・・・
著者: Yukiko Tsushima, Akira Miyauchi, Yasuhiro Ito, Takumi Kudo, Hiroo Masuoka, Tomonori Yabuta, Mitsuhiro Fukushima, Minoru Kihara, Takuya Higashiyama, Yuuki Takamura, Kaoru Kobayashi, Akihiro Miya, Toyone Kikumori, Tsuneo Imai, Tetsuya Kiuchi
雑誌名: Endocr J. 2013;60(7):871-6. Epub 2013 Apr 12.
Abstract/Text Although postoperative serum thyroglobulin (Tg) is a prognostic indicator for papillary thyroid carcinoma (PTC), it is unreliable when Tg antibody (TgAb) is positive. We evaluated the prognostic significance of changes in serum TgAb levels of pre- and post-total thyroidectomy in TgAb-positive PTC patients. We reviewed our medical charts of 225 TgAb-positive PTC patients in whom TgAb levels were measured before and 1-2 years after total thyroidectomy, performed between April 2002 and March 2007. We divided them into 3 groups based on changes in TgAb levels. Postoperative serum TgAb levels decreased by ≥ 50% in 181 patients (80.4%) (Group 1), by <50% in 22 patients (9.8%) (Group 2), and increased in 22 patients (9.8%) (Group 3). During the follow-up, 3 patients died of the disease and 14 patients had recurrences. All 3 patients who died of PTC were seen only in Groups 2 and 3. Groups 2 and 3 showed similar prognostic outcomes, thus were analyzed together as Group 2+3. Group 1 had significantly better lymph node recurrence-free survival and distant recurrence-free survival than Group 2+3 (96.9% vs. 90.5%, p <0.001, and 98.9% vs. 90.1%, p = 0.004, respectively at 5 years). Multivariate analyses on prognostic factors revealed that classification to Group 2+3 was the strongest indicator for poor prognosis. The present results suggest that changes in TgAb levels following total thyroidectomy can be an important dynamic prognostic factor of PTC patients. Prospective periodical measurements of TgAb are necessary to confirm these findings.

PMID 23585494  Endocr J. 2013;60(7):871-6. Epub 2013 Apr 12.
著者: Amy Y Chen, Ahmedin Jemal, Elizabeth M Ward
雑誌名: Cancer. 2009 Aug 15;115(16):3801-7. doi: 10.1002/cncr.24416.
Abstract/Text BACKGROUND: Studies have reported an increasing incidence of thyroid cancer since 1980. One possible explanation for this trend is increased detection through more widespread and aggressive use of ultrasound and image-guided biopsy. Increases resulting from increased detection are most likely to involve small primary tumors rather than larger tumors, which often present as palpable thyroid masses. The objective of the current study was to investigate the trends in increasing incidence of differentiated (papillary and follicular) thyroid cancer by size, age, race, and sex.
METHODS: Cases of differentiated thyroid cancer (1988-2005) were analyzed using the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) dataset. Trends in incidence rates of papillary and follicular cancer, race, age, sex, primary tumor size (<1.0 cm, 1.0-2.9 cm, 3.0-3.9 cm, and >4 cm), and SEER stage (localized, regional, distant) were analyzed using joinpoint regression and reported as the annual percentage change (APC).
RESULTS: Incidence rates increased for all sizes of tumors. Among men and women of all ages, the highest rate of increase was for primary tumors <1.0 cm among men (1997-2005: APC, 9.9) and women (1988-2005: APC, 8.6). Trends were similar between whites and blacks. Significant increases also were observed for tumors > or =4 cm among men (1988-2005: APC, 3.7) and women (1988-2005: APC, 5.70) and for distant SEER stage disease among men (APC, 3.7) and women (APC, 2.3).
CONCLUSIONS: The incidence rates of differentiated thyroid cancers of all sizes increased between 1988 and 2005 in both men and women. The increased incidence across all tumor sizes suggested that increased diagnostic scrutiny is not the sole explanation. Other explanations, including environmental influences and molecular pathways, should be investigated.

PMID 19598221  Cancer. 2009 Aug 15;115(16):3801-7. doi: 10.1002/cncr.2・・・
著者: Shiro Noguchi, Hiroto Yamashita, Shinya Uchino, Shin Watanabe
雑誌名: World J Surg. 2008 May;32(5):747-53. doi: 10.1007/s00268-007-9453-0.
Abstract/Text BACKGROUND: Papillary microcarcinoma (PMC) is increasing in incidence because of diagnosis by ultrasound-guided fine-needle aspiration cytology.
METHODS: Between January 1966 and December 1995, we treated 6019 patients with papillary cancer; among them, 2070 patients with PMC were studied.
RESULTS: PMC is essentially very similar to papillary cancer that is 11 mm or larger and has a very good prognosis. Smaller tumors and younger patients have a better prognosis. Among PMC, larger tumors (6-10 mm) recur in 14% at 35 years compared with 3.3% in patients with smaller tumors. Patients older than 55 years have recurrence in 40% at 30 years, with a worse prognosis than younger patients who have a recurrence rate of less than 10%. Extracapsular invasion by the primary tumor also has a higher recurrence rate. The majority of recurrences are in the neck. Therefore, annual ultrasound of the neck is effective for recurrence surveillance.
CONCLUSION: Papillary microcarcinoma is similar to larger papillary carcinomas with tumor characteristics and age-based recurrence rate that extends for many years, justifying long surveillance after surgery.

PMID 18264828  World J Surg. 2008 May;32(5):747-53. doi: 10.1007/s0026・・・
著者: Nobuyuki Wada, Quan-Yang Duh, Kiminori Sugino, Hiroyuki Iwasaki, Kaori Kameyama, Takashi Mimura, Koichi Ito, Hiroshi Takami, Yoshinori Takanashi
雑誌名: Ann Surg. 2003 Mar;237(3):399-407. doi: 10.1097/01.SLA.0000055273.58908.19.
Abstract/Text OBJECTIVE: To determine the frequency and pattern of lymph node metastasis (LNM) from papillary thyroid microcarcinoma (PTMC) and the results of node dissection, and to establish the optimal strategy for neck dissection in these patients.
SUMMARY BACKGROUND DATA: Most PTMCs carry a favorable prognosis, but a few present with palpable lymphadenopathy. Patients with LNM are at risk for nodal recurrence, although they do not have higher mortality. The frequency and pattern of LNM from PTMC and the results of node dissection are not well established.
METHODS: The frequency and pattern of LNM from 259 PTMCs were analyzed according to the size and location of the primary tumor. Of the 259, 24 with palpable nodes underwent therapeutic node dissection and the other 235 patients without palpable nodes underwent prophylactic node dissection. The authors compared the results of node dissection between the therapeutic group and the prophylactic group, and between PTMCs 5 mm or smaller and PTMCs larger than 5 mm. The authors also compared nodal recurrence between the prophylactic group and a no-lymph-node-dissection group (155 PTMCs).
RESULTS: Overall, 64.1% (166/259) and 44.5% (93/209) had node involvement of the central and ipsilateral lateral compartment, respectively. Pretracheal (43.2%), ipsilateral central (36.3%), and ipsilateral mid-lower (37.8%) jugular were more commonly involved. LNM was more frequent in the therapeutic group than in the prophylactic group (95.8% vs. 60.9% for central compartment, 83.3% vs. 39.5% for ipsilateral lateral compartment). Nodal recurrence was more common in the therapeutic group than in the prophylactic group (16.7% vs. 0.43%), but did not differ between the prophylactic group and the no-dissection group (0.43% vs. 0.65%). The tumor size did not influence nodal recurrence. Nodal recurrence preferentially occurred in ipsilateral mid-lower jugular nodes.
CONCLUSIONS: Patients who have PTMC presenting with palpable lymphadenopathy should have therapeutic node dissection. Prophylactic node dissection is not beneficial in those without palpable lymphadenopathy.

PMID 12616125  Ann Surg. 2003 Mar;237(3):399-407. doi: 10.1097/01.SLA.・・・
著者: Yasuhiro Ito, Takashi Uruno, Keiichi Nakano, Yuuki Takamura, Akihiro Miya, Kaoru Kobayashi, Tamotsu Yokozawa, Fumio Matsuzuka, Seiji Kuma, Kanji Kuma, Akira Miyauchi
雑誌名: Thyroid. 2003 Apr;13(4):381-7. doi: 10.1089/105072503321669875.
Abstract/Text The recent prevalence of ultrasound-guided fine-needle aspiration biopsy has resulted in a marked increase in the number of patients with papillary microcarcinoma (maximum diameter,
PMID 12804106  Thyroid. 2003 Apr;13(4):381-7. doi: 10.1089/10507250332・・・
著者: Yasuhiro Ito, Akira Miyauchi, Hiroyuki Inoue, Mitsuhiro Fukushima, Minoru Kihara, Takuya Higashiyama, Chisato Tomoda, Yuuki Takamura, Kaoru Kobayashi, Akihiro Miya
雑誌名: World J Surg. 2010 Jan;34(1):28-35. doi: 10.1007/s00268-009-0303-0.
Abstract/Text BACKGROUND: The recent development and spread of ultrasonography and ultrasonography-guided fine needle aspiration biopsy (FNAB) has facilitated the detection of small papillary microcarcinomas of the thyroid measuring 1 cm or less (PMC). The marked difference in prevalence between clinical thyroid carcinoma and PMC detected on mass screening prompted us to observe PMC unless the lesion shows unfavorable features, such as location adjacent to the trachea or on the dorsal surface of the thyroid possibly invading the recurrent laryngeal nerve, clinically apparent nodal metastasis, or high-grade malignancy on FNAB findings. In the present study we report comparison of the outcomes of 340 patients with PMC who underwent observation and the prognosis of 1,055 patients who underwent immediate surgery without observation.
METHODS: Between 1993 and 2004, 340 patients underwent observation and 1,055 underwent surgical treatment without observation. These 1,395 patients were enrolled in the present study. Observation periods ranged from 18 to 187 months (average 74 months).
RESULTS: The proportions of patients whose PMC showed enlargement by 3 mm or more were 6.4 and 15.9% on 5-year and 10-year follow-up, respectively. Novel nodal metastasis was detected in 1.4% at 5 years and 3.4% at 10 years. There were no factors related to patient background or clinical features linked to either tumor enlargement or the novel appearance of nodal metastasis. After observation 109 of the 340 patients underwent surgical treatment for various reasons, and none of those patients showed carcinoma recurrence. In patients who underwent immediate surgical treatment, clinically apparent lateral node metastasis (N1b) and male gender were recognized as independent prognostic factors of disease-free survival.
CONCLUSIONS: Papillary microcarcinomas that are not associated with unfavorable features can be candidates for observation regardless of patient background and clinical features. If there are subsequent signs of progression, such as tumor enlargement and novel nodal metastasis, it would not be too late to perform surgical treatment. Even though the primary tumor is small, careful surgical treatment including therapeutic modified neck dissection is necessary for N1b PMC patients.

PMID 20020290  World J Surg. 2010 Jan;34(1):28-35. doi: 10.1007/s00268・・・
著者: Iwao Sugitani, Kazuhisa Toda, Keiko Yamada, Noriko Yamamoto, Motoko Ikenaga, Yoshihide Fujimoto
雑誌名: World J Surg. 2010 Jun;34(6):1222-31. doi: 10.1007/s00268-009-0359-x.
Abstract/Text BACKGROUND: Papillary microcarcinoma (PMC) of the thyroid generally follows a benign clinical course. However, treatment strategies remain controversial. According to our previous retrospective review of 178 patients with PMC who underwent surgery between 1976 and 1993, the most significant risk factors affecting cancer-specific survival were clinical symptoms at presentation due to invasion or metastasis. Distant metastasis and cancer-specific death were never seen postoperatively for 148 cases (83%) of asymptomatic PMC without clinically apparent (>or=1 cm) lymph node metastasis or recurrent nerve palsy. Based on these results, we identified three biologically different types of PMC that should be treated differently. Type I comprises incidentally detected PMC without any symptoms, which is harmless and the lowest-risk cancer. Conservative follow-up with ultrasonography every 6 or 12 months is feasible. Type II involves the early stage of the usual low-risk papillary carcinoma. This can be treated by lobectomy when increasing size is noted during conservative follow-up. Type III comprises clinically symptomatic PMC, representing a high-risk cancer. Immediate wider resection followed by radioiodine treatment and suppression of thyroid-stimulating hormone is recommended.
METHODS: Since 1995, we have been conducting a prospective clinical trial of nonsurgical observation for asymptomatic PMC. As of 2008, 230 of 244 candidates (94%) have decided to accept this policy, whereas 56 patients underwent surgery for symptomatic PMC between 1976 and 2006.
RESULTS: Nonsurgical observation for a mean of 5 (range, 1-17) years for 300 lesions of asymptomatic PMC revealed that 22 (7%) had increased in size, 269 (90%) were unchanged, and 9 (3%) had decreased. No patients developed extrathyroidal invasion or distant metastasis. Three patients (1%) who developed apparent lymph node metastasis and nine patients (4%) in whom tumor increased in size eventually received surgery after 1-12 years of follow-up. No recurrences have been identified postoperatively. Conversely, 10-year cause-specific survival for symptomatic PMC was 80%. Multivariate analysis identified extrathyroidal invasion, large lymph node metastasis (>or=2 cm), and poorly differentiated component as significantly related to adverse outcomes.
CONCLUSIONS: Nonsurgical observation seems to represent an attractive alternative to surgery for asymptomatic PMC. Almost 95% of asymptomatic PMC patients are type I, and another 5% are type II and can be treated with conservative surgery. A small number of PMCs with bulky lymph node metastasis or extrathyroidal invasion are high-risk type III and require aggressive treatment.

PMID 20066418  World J Surg. 2010 Jun;34(6):1222-31. doi: 10.1007/s002・・・
著者: Yasuhiro Ito, Akira Miyauchi, Minoru Kihara, Takuya Higashiyama, Kaoru Kobayashi, Akihiro Miya
雑誌名: Thyroid. 2014 Jan;24(1):27-34. doi: 10.1089/thy.2013.0367. Epub 2013 Nov 14.
Abstract/Text BACKGROUND: We showed previously that subclinical low-risk papillary thyroid microcarcinoma (PTMC) could be observed without immediate surgery. Patient age is an important prognostic factor of clinical papillary thyroid carcinoma (PTC). In this study, we investigated how patient age influences the observation of low-risk PTMC.
METHODS: Between 1993 and 2011, 1235 patients with low-risk PTMC chose observation without immediate surgery. They were followed periodically with ultrasound examinations. These patients were enrolled in this study. We divided them into three subsets based on age at the beginning of observation: young (<40 years), middle-aged (40-59 years), and old patients (≥60 years). Observation periods ranged from 18 to 227 months (average 75 months).
RESULTS: We set three parameters for the evaluation of PTMC progression: (i) size enlargement, (ii) novel appearance of lymph-node metastasis, and (iii) progression to clinical disease (tumor size reaching 12 mm or larger, or novel appearance of nodal metastasis). The proportion of patients with PTMC progression was lowest in the old patients and highest in the young patients. On multivariate analysis, young age was an independent predictor of PTMC progression. However, none of the 1235 patients showed distant metastasis or died of PTC during observation. Although only 51 patients (4%) underwent thyrotropin (TSH) suppression based on physician preference, the PTMC of all patients enrolled in this TSH suppression study, except one, were clinically stable. To date, 191 patients underwent surgery for various reasons after observation. None showed recurrence except for one in the residual thyroid, and none died of PTC after surgery.
CONCLUSIONS: Old patients with subclinical low-risk PTMC may be the best candidates for observation. Although PTMC in young patients may be more progressive than in older patients, it might not be too late to perform surgery after subclinical PTMC has progressed to clinical disease, regardless of patient age.

PMID 24001104  Thyroid. 2014 Jan;24(1):27-34. doi: 10.1089/thy.2013.03・・・
著者: Hitomi Oda, Akira Miyauchi, Yasuhiro Ito, Kana Yoshioka, Ayako Nakayama, Hisanori Sasai, Hiroo Masuoka, Tomonori Yabuta, Mitsuhiro Fukushima, Takuya Higashiyama, Minoru Kihara, Kaoru Kobayashi, Akihiro Miya
雑誌名: Thyroid. 2016 Jan;26(1):150-5. doi: 10.1089/thy.2015.0313. Epub 2015 Nov 5.
Abstract/Text BACKGROUND: The incidence of papillary microcarcinoma (PMC) of the thyroid is rapidly increasing globally, making the management of PMC an important clinical issue. Excellent oncological outcomes of active surveillance for low-risk PMC have been reported previously. Here, unfavorable events following active surveillance and surgical treatment for PMC were studied.
METHODS: From February 2005 to August 2013, 2153 patients were diagnosed with low-risk PMC. Of these, 1179 patients chose active surveillance and 974 patients chose immediate surgery. The oncological outcomes and the incidences of unfavorable events of these groups were analyzed.
RESULTS: In the active surveillance group, 94 patients underwent surgery for various reasons; tumor enlargement and the appearance of novel lymph node metastases were the reasons in 27 (2.3%) and six patients (0.5%), respectively. One of the patients with conversion to surgery had nodal recurrence, and five patients in the immediate surgery group had a recurrence in a cervical node or unresected thyroid lobe. All of these recurrences were successfully treated. None of the patients had distant metastases, and none died of the disease. The immediate surgery group had significantly higher incidences of transient vocal cord paralysis (VCP), transient hypoparathyroidism, and permanent hypoparathyroidism than the active-surveillance group did (4.1% vs. 0.6%, p < 0.0001; 16.7% vs. 2.8%, p < 0.0001; and 1.6% vs. 0.08%, p < 0.0001, respectively). Permanent VCP occurred only in two patients (0.2%) in the immediate surgery group. The proportion of patients on L-thyroxine for supplemental or thyrotropin (TSH)-suppressive purposes was significantly larger in the immediate surgery group than in the active surveillance group (66.1% vs. 20.7%, p < 0.0001). The immediate surgery group had significantly higher incidences of postsurgical hematoma and surgical scar in the neck compared with the active surveillance group (0.5% vs. 0%, p < 0.05; and 8.0% vs. 100%, p < 0.0001, respectively).
CONCLUSIONS: The oncological outcomes of the immediate surgery and active surveillance groups were similarly excellent, but the incidences of unfavorable events were definitely higher in the immediate surgery group. Thus, active surveillance is now recommended as the best choice for patients with low-risk PMC.

PMID 26426735  Thyroid. 2016 Jan;26(1):150-5. doi: 10.1089/thy.2015.03・・・
著者: Hitomi Oda, Akira Miyauchi, Yasuhiro Ito, Hisanori Sasai, Hiroo Masuoka, Tomonori Yabuta, Mitsuhiro Fukushima, Takuya Higashiyama, Minoru Kihara, Kaoru Kobayashi, Akihiro Miya
雑誌名: Endocr J. 2017 Jan 30;64(1):59-64. doi: 10.1507/endocrj.EJ16-0381. Epub 2016 Sep 22.
Abstract/Text The incidence of thyroid cancer is increasing rapidly in many countries, resulting in rising societal costs of the care of thyroid cancer. We reported that the active surveillance of low-risk papillary microcarcinoma had less unfavorable events than immediate surgery, while the oncological outcomes of these managements were similarly excellent. Here we calculated the medical costs of these two managements. We created a model of the flow of these managements, based on our previous study. The flow and costs include the step of diagnosis, surgery, prescription of medicine, recurrence, salvage surgery for recurrence, and care for 10 years after the diagnosis. The costs were calculated according to the typical clinical practices at Kuma Hospital performed under the Japanese Health Care Insurance System. If conversion surgeries were not considered, the 'simple cost' of active surveillance for 10 years was 167,780 yen/patient. If there were no recurrences, the 'simple cost' of immediate surgery was calculated as 794,770 yen/patient to 1,086,070 yen/patient, depending on the type of surgery and postoperative medication. The 'simple cost' of surgery was 4.7 to 6.5 times the 'simple cost' of surveillance. When conversion surgeries and recurrence were considered, the 'total cost' of active surveillance for 10 years became 225,695 yen/patient. When recurrence were considered, the 'total cost' of immediate surgery was 928,094 yen/patient, which was 4.1 times the 'total cost' of the active surveillance. At Kuma Hospital in Japan, the 10-year total cost of immediate surgery was 4.1 times expensive than active surveillance.

PMID 27667647  Endocr J. 2017 Jan 30;64(1):59-64. doi: 10.1507/endocrj・・・
著者: Akira Miyauchi, Takumi Kudo, Yasuhiro Ito, Hitomi Oda, Hisanori Sasai, Takuya Higashiyama, Mitsuhiro Fukushima, Hiroo Masuoka, Minoru Kihara, Akihiro Miya
雑誌名: Surgery. 2018 Jan;163(1):48-52. doi: 10.1016/j.surg.2017.03.028. Epub 2017 Nov 2.
Abstract/Text BACKGROUND: We reported that a minority of patients with low-risk papillary microcarcinoma of the thyroid showed disease progression during active surveillance and that older patients had significantly lower disease progression rates than younger patients. Here, we estimated lifetime (≤85 years old) probabilities of disease progression during active surveillance according to the age at presentation based on age decade-specific disease progression rates.
METHODS: From 1993-2013, 1,211 low-risk papillary microcarcinoma patients aged 20-79 years underwent active surveillance at Kuma Hospital. We calculated the disease progression rate at the 10-year point of active surveillance for each age-decade group (20s to 70s) with the Kaplan-Meier method. The lifetime disease progression probability for each age group was calculated as (1 - cumulative probability of progression-free survival calculated with age decade-specific disease progression rates) until the patients reached their 80s (i.e., 85 years on average).
RESULTS: The age decade-specific disease progression rates at 10 years of active surveillance were 36.9% (20s), 13.5% (30s), 14.5% (40s), 5.6% (50s), 6.6% (60s), and 3.5% (70s); the respective lifetime disease progression probabilities were 60.3%, 37.1%, 27.3%, 14.9%, 9.9% and 3.5% according to the age at presentation.
CONCLUSION: The estimated lifetime disease progression probabilities of papillary microcarcinoma during active surveillance vary greatly according to the age at presentation.

Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
PMID 29103582  Surgery. 2018 Jan;163(1):48-52. doi: 10.1016/j.surg.201・・・
著者: Akira Miyauchi, Takumi Kudo, Yasuhiro Ito, Hitomi Oda, Masatoshi Yamamoto, Hisanori Sasai, Takuya Higashiyama, Hiroo Masuoka, Mitsuhiro Fukushima, Minoru Kihara, Akihiro Miya
雑誌名: Surgery. 2019 Jan;165(1):25-30. doi: 10.1016/j.surg.2018.07.045. Epub 2018 Nov 6.
Abstract/Text BACKGROUND: We report on the growth of papillary microcarcinoma during active surveillance and before clinical presentation.
METHODS: We conducted a retrospective study of 169 patients with papillary microcarcinoma who were enrolled in active surveillance at our hospital between 2000 and 2004. Patients were followed for a median of 10.1 years using serial ultrasonography (median, 12 examinations), used to calculate the tumor doubling time. To contextualize tumor growth rates during active surveillance, we calculated the hypothetical tumor doubling time before clinical presentation. To resolve the limitations in tumor doubling time, tumor doubling rates were inversely transformed into doubling rates.
RESULTS: The doubling rates (per year) during active surveillance (median: 0.0) were >0.5, 0.1 to 0.5, -0.1 to 0.1, and <-0.1 in 5, 38, 97, and 29 cases, respectively. The proportions of tumors with rather rapid growth, slow growth, stable, and a decrease in size were 3%, 22%, 57%, and 17%, respectively.
CONCLUSION: Tumor growth of papillary microcarcinomas varies from rather rapid growth to a decrease in size during active surveillance.

Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
PMID 30413323  Surgery. 2019 Jan;165(1):25-30. doi: 10.1016/j.surg.201・・・
著者: Yasuhiro Ito, Akira Miyauchi
雑誌名: World J Surg. 2008 May;32(5):729-39. doi: 10.1007/s00268-007-9315-9.
Abstract/Text BACKGROUND: The lateral compartment frequently demonstrates metastasis from thyroid carcinoma. In contrast to that for central lymph node dissection, the indication for lateral node dissection remains controversial.
METHODS: In this review we evaluate the indication of lateral lymph node dissection in papillary and follicular carcinomas based on the findings of previous reports, including those from our institute.
RESULTS: Lymph node metastasis and recurrence at the lymph node are common events in papillary carcinoma. In particular, the lymph node recurrence rate in patients with clinically apparent lateral node metastasis (N1b) is high, not only in compartments that have not been dissected but also in those previously dissected, even if therapeutic lateral node dissection is performed. For N0 or N1a papillary carcinomas, male gender, being 55 or more years of age, a tumor larger than 3 cm, and massive extrathyroid extension are independent risk factors of lymph node recurrence, and patients with tumors having two or more of these clinicopathologic features showed high lymph node recurrence rates even if they underwent prophylactic lateral node dissection. In follicular carcinoma, node metastasis and recurrence at the node are rare events but they occasionally can be observed, especially in tumors with massive extrathyroid extension and poor differentiation.
CONCLUSION: N1b is an absolute indication for lateral lymph node dissection. Prophylactic lateral node dissection is also recommended in N0 or N1a papillary carcinoma, if the lesion shows two or more of the aggressive characteristics indicated above. For follicular carcinoma, prophylactic node dissection is not mandatory but can be an option for tumors demonstrating aggressive characteristics or histologic types.

PMID 18064515  World J Surg. 2008 May;32(5):729-39. doi: 10.1007/s0026・・・
著者: Jong-Lyel Roh, Jin-Man Kim, Chan Il Park
雑誌名: Ann Surg Oncol. 2008 Apr;15(4):1177-82. doi: 10.1245/s10434-008-9813-5. Epub 2008 Feb 6.
Abstract/Text BACKGROUND: The pattern of lateral cervical metastases from papillary thyroid carcinoma (PTC) has been reported without a clear understanding of the distribution of central nodes at risk. The present study evaluated the pattern of central and lateral cervical metastases from PTC with respect to recently defined neck sublevels and subsites.
METHODS: Between 2003 and 2006, 52 consecutive patients with lateral cervical metastases from previously untreated PTC underwent total thyroidectomy and therapeutic comprehensive neck dissection of the central and lateral compartments, including five bilateral neck dissections. Neck dissection specimens were separately obtained for analyzing lymph node involvement with respect to neck sublevels and subsites.
RESULTS: For the lateral compartment, 75.9% of cases showed metastatic disease at level IV, 72.2% at IIa and III, 16.7% at IIb, 13.0% at Vai, 3.7% at Ib and Vb, and 0% at Vas. For the central compartment, 84.6% of cases showed metastatic disease at the ipsilateral paratracheal nodal site, 46.2% at the superior mediastinal, 30.8% at the pretracheal, and 8.9% at the contralateral paratracheal site. Forty-six of 57 lateral neck dissection samples (80.7%) showed multilevel disease, and skip lateral metastasis was found in five patients (9.6%). Level I and V involvements were always associated with multilevel disease.
CONCLUSIONS: Lateral cervical metastasis from PTC is commonly associated with multilevel disease and central nodal involvement. Neck dissection including ipsilateral central and lateral compartments may be the optimal treatment for these patients.

PMID 18253801  Ann Surg Oncol. 2008 Apr;15(4):1177-82. doi: 10.1245/s1・・・
著者: N R Caron, Y Y Tan, J B Ogilvie, F Triponez, E S Reiff, E Kebebew, Q Y Duh, O H Clark
雑誌名: World J Surg. 2006 May;30(5):833-40. doi: 10.1007/s00268-005-0358-5.
Abstract/Text BACKGROUND: There is ongoing controversy as to the indications for and extent of lateral cervical lymphadenectomy for patients with papillary thyroid cancer (PTC). While most now agree that prophylactic lymph node dissections (LND) play no role, at the University of California, San Francisco (UCSF) we limit LND selectively on a level by level basis, and resect only the levels thought to harbor disease or to be at increased risk of metastases. This initial 'selective LND' usually includes levels III and IV (due to the well-documented increased likelihood of metastases to these levels) and levels I, II, and V are included when there is clinical or radiological evidence of disease or increased risk of it.
METHODS: A retrospective review of the clinical charts and hospital records of 106 consecutive patients who had metastatic PTC and who underwent at least one lateral cervical LND at UCSF between January 1995 and December 2003 was carried out. Data were collected to assess which patients had levels I, II, and/or V included in their initial ipsilateral and/or contralateral LND and to determine the recurrence rates at these levels if they had previously been excised compared with if they had not. Chi-squared and Fisher exact tests were utilized for statistical comparison, where appropriate.
RESULTS: A total of 140 initial lateral LND were performed: 104 ipsilateral and 36 contralateral. In these initial LND, 3.9%, 72.5%, and 18.6% of patients had levels I, II, and V resected on the ipsilateral side, and 2.9%, 60.0%, and 37.1% of patients had levels I, II, and V resected on the contralateral side. Recurrence at levels I and V was uncommon in all patient populations. Recurrence at level II was 19% ipsilaterally and 10% contralaterally when the level was previously resected and 21% ipsilaterally and 14% contralaterally when the level was not previously resected. There was no statistically significant difference in recurrence at level II when the level had previously been resected compared with when it had not.
CONCLUSIONS: If utilized in the appropriate patient population, a selective approach to lateral cervical LND for PTC can be a successful alternative to the routine modified radical LND. Levels I and V do not require resection unless there is clinical or radiological evidence of disease. Guidelines for which patients may be considered for this less aggressive approach to level II nodal metastases are suggested.

PMID 16555024  World J Surg. 2006 May;30(5):833-40. doi: 10.1007/s0026・・・
著者: Yun-Sung Lim, Jin-Choon Lee, Yoon Se Lee, Byung-Joo Lee, Soo-Geun Wang, Seok-Man Son, In-Ju Kim
雑誌名: Surgery. 2011 Jul;150(1):116-21. doi: 10.1016/j.surg.2011.02.003. Epub 2011 Apr 20.
Abstract/Text BACKGROUND: Papillary thyroid carcinoma (PTC) frequently metastasizes to the regional neck; skip metastasis (metastasis to the lateral compartment in the absence of central disease) is uncommon. This prospective study was to evaluate the incidence of occult lateral neck metastasis (LNM) and elucidated the factors that predict LNM in PTC with central neck metastasis (CNM) by performing prophylactic selective lateral neck dissection (SND).
METHODS: Sixty-two patients with PTC without clinical LNM underwent total thyroidectomy with central compartment neck dissection and prophylactic SND consecutively after ipsilateral CNM was confirmed by intraoperative frozen biopsy.
RESULTS: The incidence of occult LNM in PTC was 55%. Patients with LNM had a larger primary tumor and more positive ipsilateral and bilateral central lymph nodes than patients without LNM. There were no differences between patients with and without LNM with regard to age and extrathyroidal extension. The incidence of occult LNM increased significantly as the number of metastatic ipsilateral and bilateral lymph nodes increased. Independent risk factors for occult LNM were tumor size and the number of positive bilateral lymph nodes (odds ratio [OR] = 1.449; OR = 1.110, respectively). The most common metastatic site was level III (68%: 23/34), followed by level IV (59%: 20/34) and level II (21%: 7/34).
CONCLUSION: The important risk factors for LNM in PTC are primary tumor size and the number of positive bilateral central lymph nodes. Prophylactic SND may be considered in selected patients with a large number of positive central lymph nodes and large tumors.

Copyright © 2011 Mosby, Inc. All rights reserved.
PMID 21507446  Surgery. 2011 Jul;150(1):116-21. doi: 10.1016/j.surg.20・・・
著者: S Noguchi, N Murakami, H Yamashita, M Toda, H Kawamoto
雑誌名: Arch Surg. 1998 Mar;133(3):276-80.
Abstract/Text OBJECTIVE: To ascertain whether modified radical neck dissection offers a survival advantage for some subsets of patients with papillary cancer of the thyroid.
DESIGN: A retrospective cohort study of 2966 patients curatively treated at the Noguchi Thyroid Clinic and Hospital Foundation, Oita, Japan, between 1946 and 1991.
SETTING: A center for the treatment of thyroid disease, where about 1400 thyroid operations are performed per year.
PATIENTS: Between 1946 and 1991, patients with papillary cancer whose primary tumor was 1 cm or larger and who were curatively treated were studied. Of the 2859 patients, 72.1% underwent modified radical neck dissection, 8.5% underwent partial node excision, and 19.4% underwent no node excision.
RESULTS: A univariate analysis revealed a subset of patients who benefited from modified radical neck dissection. A multivariate analysis revealed that sex (P<.001), age at the time of the operation (P<.001), size of the primary tumor (P<.001), extrathyroidal invasion (P<.001), and the presence of nodal metastasis (P<.01) are significant risk factors.
CONCLUSION: Patients with nodal metastasis, patients in whom the primary tumor invades beyond the thyroid capsule, and women older than 60 years can benefit from modified radical neck dissection.

PMID 9517740  Arch Surg. 1998 Mar;133(3):276-80.
著者: Iwao Sugitani, Yoshihide Fujimoto, Keiko Yamada, Noriko Yamamoto
雑誌名: World J Surg. 2008 Nov;32(11):2494-502. doi: 10.1007/s00268-008-9711-9.
Abstract/Text BACKGROUND: Although many patients with papillary thyroid carcinoma (PTC) display associated cervical lymph node metastases (LNM), the optimal extent of lymph node dissection (LND) remains a matter of debate. Since 1993, we have performed cervical LND based on the preoperative suspicion of LNM by ultrasonography (US). We prospectively analyzed the outcomes of our "selective" LND to determine when prophylactic lateral neck dissection is advisable.
METHODS: Prospective analysis was conducted for 361 consecutive patients with PTC who received initial surgery between 1993 and 2001. Mean duration of follow-up was 8.1 years. Dissection of the central compartment only was performed for patients with LNM in the central zone only and for patients with no LNM detected by US (Group A). Modified radical lateral neck dissection (MND; combined with central compartment dissection) was performed for patients diagnosed with lateral neck LNM (Group B).
RESULTS: Pathological LNM was found in 136 of 231 patients in Group A (59%). As for the accuracy of US diagnosis, positive predictive value was 82%. Nodal recurrences, occurring all in the lateral cervical region associated with one case of contralateral paratracheal region, was seen in 18 patients (8%) and 10-year nodal disease-free survival was 91%. Univariate analysis revealed true positive diagnosis by US, large primary tumor (> or = 4 cm), primary tumor located in the upper part of the thyroid lobe, presence of distant metastasis, extrathyroidal invasion of the primary tumor, and a poorly differentiated component of the primary tumor as significant risk factors for nodal recurrence. Among the risk factors that could be diagnosed preoperatively, distant metastasis (risk ratio, 46; p = 0.01) and large primary tumor (risk ratio, 3.6; p = 0.03) were the most important factors under multivariate analysis. Of the other 130 patients in Group B, only 3 patients had no pathological LNM (positive predictive value, 98%). Twenty-six patients (20%) developed nodal recurrence, with a 10-year nodal disease-free survival of 76%. Age (50 years or older), large nodal metastasis (> or = 3 cm), extrathyroidal invasion, and higher serum thyroglobulin level (> or =320 ng/ml) represented significant factors for nodal recurrence.
CONCLUSIONS: When preoperative US shows no LNM or indicates only LNM in the central compartment, dissection of the central compartment alone offers a sufficient alternative to routine prophylactic MND. However, patients with PTC demonstrating large primary tumor and/or distant metastasis were high-risk for recurrence in the lateral cervical compartment. We recommend prophylactic MND to reduce nodal recurrence for those patients.

PMID 18784956  World J Surg. 2008 Nov;32(11):2494-502. doi: 10.1007/s0・・・
著者: Yasuhiro Ito, Takuya Higashiyama, Yuuki Takamura, Akihiro Miya, Kaoru Kobayashi, Fumio Matsuzuka, Kanji Kuma, Akira Miyauchi
雑誌名: World J Surg. 2007 Nov;31(11):2085-91. doi: 10.1007/s00268-007-9224-y.
Abstract/Text BACKGROUND: Although papillary carcinoma usually shows mild characteristics, it metastasizes and shows recurrence to the lymph node in high incidences. Of the two representative lymph node compartments to which papillary carcinoma metastasizes, the central compartment can be routinely dissected via the surgical incision made for thyroidectomy. However, the routine application of prophylactic lateral node dissection (modified radical neck dissection [MND]) remains controversial. In this study, we investigated risk factors for lymph node recurrence of papillary carcinoma to determine the appropriate application of prophylactic MND.
METHODS: We investigated risk factors for lymph node recurrence in 1,231 patients without preoperatively detectable lateral node metastasis who underwent thyroidectomy, central node dissection, and prophylactic MND for papillary carcinoma between 1987 and 1995.
RESULTS: The incidence of lateral node metastasis and the number of metastatic lateral nodes significantly increased with carcinoma size. The lymph node disease-free survival (LN-DFS) was also significantly worse in carcinoma with a maximal diameter greater than 3 cm. Massive extrathyroid extension, male gender, and age 55 years or older also reflected a poorer LN-DFS. The 10-year LN-DFS rates of patients with carcinoma having two and three or four of these features were low at 88.5% and 64.7%, respectively, although the rates of those with carcinoma having no or only one characteristic were better than 95%.
CONCLUSIONS: Prophylactic MND is recommended for cases of papillary carcinoma demonstrating two or more of the following four characteristics; male gender, age 55 years or older, maximal tumor diameter larger than 3 cm, and massive extrathyroid extension.

PMID 17885787  World J Surg. 2007 Nov;31(11):2085-91. doi: 10.1007/s00・・・
著者: N Wada, K Masudo, H Nakayama, N Suganuma, K Matsuzu, S Hirakawa, Y Rino, M Masuda, T Imada
雑誌名: Eur J Surg Oncol. 2008 Feb;34(2):202-7. doi: 10.1016/j.ejso.2007.10.001. Epub 2007 Nov 19.
Abstract/Text AIMS: To examine lymph node metastasis (LNM) from papillary thyroid carcinoma (PTC) according to clinicopathological features and outcomes associated with the nodal status.
METHODS: We reviewed 231 patients with PTC (> or =1.0cm) who underwent initial thyroidectomy with modified neck dissection. LNM was examined in the central and lateral compartment and risk factors for disease-free survival (DFS) were evaluated. Nodal status and outcomes were further evaluated in four subgroups, 19 older patients (> or =45years old) with palpable lymphadenopathy (PLA) and 134 without PLA, and 11 younger patients (<45years old) with PLA and 67 without PLA, because multivariate analysis revealed that age (p<0.05, Hazard ratio (HR) 3.51) and PLA (p<0.0001, HR 14.9) were risk factors for DFS.
RESULTS: Central and lateral LNM were found in 176 and 151 patients. Seventeen exhibited skip metastasis. Recurrence and disease death occurred in 23 and 5. In analysis of the four subgroups, recurrence was significantly frequent in older patients with PLA than in younger patients with PLA or older patients without PLA (8/19 vs. 3/11 or 12/134). Younger patients without PLA did not exhibit recurrence.
CONCLUSIONS: Prognosis is worse in older patients with PLA. Such patients should be treated carefully with a considerable treatment strategy.

PMID 18023321  Eur J Surg Oncol. 2008 Feb;34(2):202-7. doi: 10.1016/j.・・・
著者: N Sato, M Oyamatsu, Y Koyama, I Emura, Y Tamiya, K Hatakeyama
雑誌名: J Surg Oncol. 1998 Nov;69(3):151-5.
Abstract/Text BACKGROUND AND OBJECTIVES: The importance of nodal involvement as a prognostic factor in differentiated carcinoma of the thyroid gland remains controversial. We therefore attempted to confirm the prognostic factors in differentiated thyroid carcinoma, with special reference to nodal status.
PATIENTS AND METHODS: A total of 139 patients with differentiated thyroid cancer followed for 2-27 years, with a median follow-up of 7 years were studied. All patients underwent surgical resection, either subtotal, total, or lobectomy, with modified radical neck dissection. Survival was calculated using the Kaplan-Meier method.
RESULTS: Ten (7%) patients have died from thyroid cancer. Adverse prognostic factors included age >45 years (P=0.0120), the presence of distant metastases (P=0.0006), and TNM stage (P=0.0002). The number of lymph nodes dissected ranged from 6 to 92, with an average of 26. Lymph node metastases were found in 102 (73%) patients. There was no difference in survival according to the level of nodal disease by the TNM classification. Furthermore, the number of cervical lymph nodes involved had no effect on the survival.
CONCLUSION: Our results suggest that the presence of histologically confirmed lymph node metastases is not an important prognostic factor in patients with differentiated thyroid carcinoma.

PMID 9846501  J Surg Oncol. 1998 Nov;69(3):151-5.
著者: L E Tisell, B Nilsson, J Mölne, G Hansson, M Fjälling, S Jansson, U Wingren
雑誌名: World J Surg. 1996 Sep;20(7):854-9.
Abstract/Text A total of 195 patients had surgery for papillary thyroid cancer. The mean age at operation was 50 years. A microdissection technique was used for total thyroidectomy and lymph node clearance. Postoperative radioiodine tests showed no uptake or an uptake close to the background activity in 77% of the examined patients. By counting the lymph nodes removed at surgery we were able to check on the quality of the lymph node dissection. Men had a higher incidence (70%) of lymph node metastases than women (45%). Only 4% of the patients had radioiodine ablation of the thyroid remnant. The median follow-up time was 13 years. None of the patients below 45 years of age at surgery died of thyroid cancer. In the older age group eight patients died of thyroid cancer at a mean age of 75 years. Five of those who died of a thyroid carcinoma had distant metastases at diagnosis. Among patients with resectable disease, three (1.6%) died of thyroid cancer, all of whom had lived for more than 17 years after surgery. Hence longer follow-up is needed before we know the final mortality in our series. The results suggest that surgical technique and strategy can positively influence the survival of patients with papillary thyroid cancer.

PMID 8678962  World J Surg. 1996 Sep;20(7):854-9.
著者: G F Scheumann, O Gimm, G Wegener, H Hundeshagen, H Dralle
雑誌名: World J Surg. 1994 Jul-Aug;18(4):559-67; discussion 567-8.
Abstract/Text We studied the records of 342 patients with papillary thyroid carcinoma out of a total of 728 thyroid cancer patients treated at the Medical School of Hannover (MHH) from 1972 through 1992. The comprehensive data-abstracting forms were designed, and the acquired information was coded, stored, maintained, and evaluated by the Clinical Cancer Registry of the MHH. A total of 160 patients (46.8%) initially had lymph node metastases (N1 status). The N status significantly influenced recurrence (p < 0.00001) and survival (p < 0.00001). Excluding other risk factors developed by univariate and multivariate analysis, such as high age (age > 45 years, p < 0.001), tumor invasion (T4 tumor, p < 0.005), and distant metastases (M1, p < 0.001), lymph node metastases remained an independent, highly significant prognostic marker for more aggressive papillary thyroid cancer. N1 status did not influence survival of patients with T4 tumor but did influence those with T1-T3 status (p < 0.001). The influence of N1 status remained significant in patients older (p < 0.001) and younger (p < 0.05) than 45 years of age. Systematic compartment-oriented dissection of lymph node metastases improved survival (p < 0.005, T1-T3) and recurrence (p < 0.00001, T1-T3) especially in patients with T1-T3 tumors. In conclusion, lymph node metastases with a significant incidence at a young age and male sex had a substantial effect on survival and recurrence especially in those with tumor status T1-T3. Systematic compartment-oriented dissection of the lymph node metastases results in better survival and a lower recurrence rate.

PMID 7725745  World J Surg. 1994 Jul-Aug;18(4):559-67; discussion 567・・・
著者: D Simon, P E Goretzki, J Witte, H D Röher
雑誌名: World J Surg. 1996 Sep;20(7):860-6; discussion 866.
Abstract/Text Total thyroidectomy has become the routine procedure for treatment of differentiated thyroid carcinoma. However, the necessity of unilateral or bilateral neck dissection is far less standardized. Our usual procedure has been to perform a routine neck dissection in T4 tumors and in all other tumor stages only in the presence of positive diagnostic or intraoperative findings. The results concerning regional tumor recurrence in cervical lymph nodes subsequent to thyroidectomy are studied and discussed. Between April 1986 and December 1992 a group of 252 patients were operated on for differentiated thyroid carcinoma (DTC) (176 papillary, 76 follicular). Postoperative treatment included radioiodine therapy as a rule in all patients more than stage T1, and follow-up encompassed thyroglobulin measurements, cervical ultrasonography, and radioiodine scintigraphy. After a mean follow-up of 6.9 years, 77 (31%) of the patients underwent reoperation because of regional tumor recurrence [46 of 176 (26%) papillary, 31 of 76 (41%) follicular]. In papillary thyroid cancer a significant difference could be demonstrated between patients with thyroidectomy only versus thyroidectomy plus neck dissection in all tumor stages (T2, 13 of 29 (45%) versus 1 of 34 (3%); T3, 10 of 13 (77%) versus 4 of 11 (36%); T4, 6 of 8 (75%) versus 6 of 18 (33%) (p < 0.0001). Similar results could be achieved for follicular thyroid cancer, showing statistical significance with regard to operative procedure (p < 0.009). Our experience demonstrates a positive correlation of regional tumor recurrence with increasing tumor stage for both histologic tumor types. The high rate of regional recurrence justifies a more radical approach, including neck dissection at the initial operation. The impact on survival, however, must be proved by further evaluation.

PMID 8678963  World J Surg. 1996 Sep;20(7):860-6; discussion 866.
著者: Matthew L White, Paul G Gauger, Gerard M Doherty
雑誌名: World J Surg. 2007 May;31(5):895-904. doi: 10.1007/s00268-006-0907-6.
Abstract/Text BACKGROUND: There has been renewed interest in extensive lymph node dissection for papillary thyroid cancer (PTC), and a number of reports have been published concerning compartment-oriented dissection of regional lymph nodes in PTC. A comprehensive review of this body of literature using evidence-based methodology is pending.
METHODS: Systematic review of the literature using evidence-based criteria.
RESULTS: Issue 1: Systematic compartment-oriented central lymph node dissection (CLND) may decrease recurrence of PTC (Levels IV and V data, no recommendation) and likely improves disease-specific survival (grade C recommendation). Limited level III data suggest survival benefit with the addition of prophylactic dissection to thyroidectomy (grade C recommendation). The addition of CLND to total thyroidectomy can significantly reduce levels of serum thyroglobulin and increase rates of athyroglobulinemia (level IV data, no recommendation). Issue 2: There may be a higher rate of permanent hypoparathyroidism and unintentional permanent nerve injury when CLND is performed with total thyroidectomy than for total thyroidectomy alone (grade C recommendation). Issue 3: Reoperation in the central neck compartment for recurrent PTC may increase the risk of hypoparathyroidism and unintentional nerve injury when compared with total thyroidectomy with or without CLND (grade C recommendation), supporting a more aggressive initial operation.
CONCLUSION: Evidence-based recommendations support CLND for PTC in patients under the care of experienced endocrine surgeons.

PMID 17347896  World J Surg. 2007 May;31(5):895-904. doi: 10.1007/s002・・・
著者: Tobias Carling, William D Long, Robert Udelsman
雑誌名: Curr Opin Oncol. 2010 Jan;22(1):30-4. doi: 10.1097/CCO.0b013e328333ac97.
Abstract/Text PURPOSE OF REVIEW: Differentiated thyroid cancer (DTC), with a rapidly increasing incidence is the most common endocrine malignancy, but with generally favorable survival. Total thyroidectomy with 'therapeutic' cervical lymph node dissection for involved lymph nodes is the standard of care. A more controversial topic is whether routine 'prophylactic' central lymph node dissection (CLND) in patients without evidence of lymph node metastasis should be performed in patients with DTC, as suggested by several recent management guidelines.
RECENT FINDINGS: A number of retrospective studies suggest that regional lymph node metastases are associated with tumor recurrence and adverse survival. CLND is associated with a higher rate of postoperative athyroglobulinemia and may modify the indications for radioactive iodine treatment. Current guidelines from the American Thyroid Association suggest that prophylactic CLND may be performed for papillary thyroid cancer, especially for advanced tumors (T3 and T4).
SUMMARY: Recent studies and the arguments for and against prophylactic CLND are reviewed. There is currently a trend toward more aggressive surgical therapy, including prophylactic CLND and avoidance of radioactive iodine treatment for DTC, when appropriate. Randomized prospective controlled trials are lacking at this point to determine the role of prophylactic CLND in the management of DTC.

PMID 19864950  Curr Opin Oncol. 2010 Jan;22(1):30-4. doi: 10.1097/CCO.・・・
著者: Dana M Hartl, Elisabeth Mamelle, Isabelle Borget, Sophie Leboulleux, Haïtham Mirghani, Martin Schlumberger
雑誌名: World J Surg. 2013 Aug;37(8):1951-8. doi: 10.1007/s00268-013-2089-3.
Abstract/Text BACKGROUND: Prophylactic neck dissection (PND) for papillary thyroid cancer is controversial. The objective of this study was to analyze the influence of PND on the rate of retreatment.
METHODS: In this retrospective case-control study, papillary thyroid carcinomas >10 mm without ultrasonographic evidence of nodal disease (cN0) were treated with total thyroidectomy (TT) or TT with bilateral central compartment PND. All received postoperative radioactive iodine ((131)I) and were followed for at least 1 year. We compared the rate of retreatment (surgery or (131)I).
RESULTS: Altogether, 246 patients (mean age 46 years, 78 % women) underwent TT (n = 91) or TT + PND (n = 155). The groups were similar in age, sex, tumor size, and follow-up (median 6.3 years) (p > 0.05). Overall, 11 (12 %) of the patients in the TT group underwent reoperation in the central compartment for recurrence versus 3 (2 %) in the TT + PND group (p < 0.001). There were 1.18 administrations of (131)I for the TT group versus 1.08 for the TT + PND group (p = 0.08). The average cumulative dose of (131)I was 3.9 ± 1.8 GBq for the TT group and 3.8 ± 1.3 GBq for the TT + PND group (p = 0.52). Actuarial (Kaplan-Meier) 5-year retreatment rates were 14.7 % in the TT group and 6.5 % in the TT + PND group (p = 0.01, log-rank). The rate of permanent recurrent nerve paralysis was 2 % for the TT group and 1 % for the TT + PND group (p = 0.98). The rates of permanent hypoparathyroidism were 7 versus 3 %, respectively (p = 0.12).
CONCLUSIONS: Five-year retreatment rates were lower in patients treated with PND, with no added permanent morbidity.

PMID 23677562  World J Surg. 2013 Aug;37(8):1951-8. doi: 10.1007/s0026・・・
著者: Tania Pilli, Ernesto Brianzoni, Francesca Capoccetti, Maria Grazia Castagna, Sara Fattori, Angela Poggiu, Gloria Rossi, Francesca Ferretti, Elisa Guarino, Luca Burroni, Angelo Vattimo, Claudia Cipri, Furio Pacini
雑誌名: J Clin Endocrinol Metab. 2007 Sep;92(9):3542-6. doi: 10.1210/jc.2007-0225. Epub 2007 Jul 3.
Abstract/Text OBJECTIVE: Recently, a multicenter study in differentiated thyroid cancer (DTC) patients showed that 3700 MBq 131-iodine ((131)I) after recombinant human TSH (rhTSH) had a successful thyroid ablation rate similar to that obtained after thyroid hormone withdrawal. We investigated whether 1850 MBq (131)I had a similar successful rate to 3700 MBq in patients prepared with rhTSH.
DESIGN: A total of 72 patients with DTC were randomly assigned to receive 1850 (group A, n = 36) or 3700 MBq (group B, n = 36) (131)I after rhTSH. One injection of 0.9 mg rhTSH was administered for 2 consecutive days; (131)I therapy was delivered 24 h after the last injection, followed by a posttherapy whole-body scan. Successful ablation was assessed 6-8 months later.
RESULTS: Successful ablation (no visible uptake in the diagnostic whole-body scan after rhTSH stimulation) was achieved in 88.9% of group A and B patients. Basal and rhTSH-stimulated serum thyroglobulin was undetectable (<1 ng/ml) in 78.9% of group A and 66.6% of group B patients (P = 0.46). Similar rates of ablation were obtained in both groups also in patients with node metastases.
CONCLUSION: Therapeutic (131)I activities of 1850 MBq are equally effective as 3700 MBq for thyroid ablation in DTC patients prepared with rhTSH, even in the presence of node metastases.

PMID 17609306  J Clin Endocrinol Metab. 2007 Sep;92(9):3542-6. doi: 10・・・
著者: M Chianelli, V Todino, F M Graziano, C Panunzi, D Pace, R Guglielmi, A Signore, E Papini
雑誌名: Eur J Endocrinol. 2009 Mar;160(3):431-6. doi: 10.1530/EJE-08-0669. Epub 2008 Dec 12.
Abstract/Text OBJECTIVE: (a) To compare the efficacy of low-activity (2 GBq; 54 mCi) (131)I ablation using l-thyroxine withdrawal or rhTSH stimulation, and (b) to assess the influence of thyroid remnants volume on the ablation rate.
DESIGN: Patients underwent neck ultrasound, (131)I neck scintigraphy and radioiodine uptake. Post-therapy whole body scan (WBS) was acquired after 4-6 days. Ablation was assessed after 6-12 months by WBS, Tg and TgAb following l-thyroxine withdrawal.
METHODS: Group A: preparation by L-T(4) withdrawal (37 days); 21 patients received (131)I (2.02+/-0.22 GBq; 54.6+/-5.9 mCi) and on the day of treatment, TSH, Tg, TgAb were measured; Group B: stimulation by rhTSH; 21 patients received (131)I (1.97+/-0.18 GBq; 53.2+/-4.9 mCi) 24 h after the second injection of rhTSH (0.9 mg) and TSH, Tg and TgAb were measured after 2 days.
RESULTS: At follow-up, 90.0% of patients from group A and 85.0% of patients from group B had Tg levels <1 ng/ml; no uptake was observed in 95.2% and in 90.5% of patients from group A or B respectively, with no statistical differences for both ablation criteria. Before (131)I treatment, small thyroid remnants (<1 ml) were detected by US in <25% of all patients.
CONCLUSIONS: The use of rhTSH for the preparation of low-risk patients to ablation therapy with low activities of (131)I (2 GBq; 54 mCi) is safe and effective and avoids hypothyroidism. The presence of thyroid remnants smaller than 1 ml at US evaluation had no effect on the ablation rate.

PMID 19074463  Eur J Endocrinol. 2009 Mar;160(3):431-6. doi: 10.1530/E・・・
著者: Marcia S Brose, Christopher M Nutting, Barbara Jarzab, Rossella Elisei, Salvatore Siena, Lars Bastholt, Christelle de la Fouchardiere, Furio Pacini, Ralf Paschke, Young Kee Shong, Steven I Sherman, Johannes W A Smit, John Chung, Christian Kappeler, Carol Peña, István Molnár, Martin J Schlumberger, DECISION investigators
雑誌名: Lancet. 2014 Jul 26;384(9940):319-28. doi: 10.1016/S0140-6736(14)60421-9. Epub 2014 Apr 24.
Abstract/Text BACKGROUND: Patients with radioactive iodine ((131)I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer.
METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0-2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0·5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov, number NCT00984282, and with the EU Clinical Trials Register, number EudraCT 2009-012007-25.
FINDINGS: Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10·8 months) than in the placebo group (5·8 months; hazard ratio [HR] 0·59, 95% CI 0·45-0·76; p<0·0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98·6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87·6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash or desquamation (50·2%).
INTERPRETATION: Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer.
FUNDING: Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 24768112  Lancet. 2014 Jul 26;384(9940):319-28. doi: 10.1016/S014・・・
著者: Martin Schlumberger, Makoto Tahara, Lori J Wirth, Bruce Robinson, Marcia S Brose, Rossella Elisei, Mouhammed Amir Habra, Kate Newbold, Manisha H Shah, Ana O Hoff, Andrew G Gianoukakis, Naomi Kiyota, Matthew H Taylor, Sung-Bae Kim, Monika K Krzyzanowska, Corina E Dutcus, Begoña de las Heras, Junming Zhu, Steven I Sherman
雑誌名: N Engl J Med. 2015 Feb 12;372(7):621-30. doi: 10.1056/NEJMoa1406470.
Abstract/Text BACKGROUND: Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131).
METHODS: In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety.
RESULTS: The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related.
CONCLUSIONS: Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.).

PMID 25671254  N Engl J Med. 2015 Feb 12;372(7):621-30. doi: 10.1056/N・・・
著者: Yasuhiro Ito, Akira Miyauchi, Mitsuru Ito, Tomonori Yabuta, Hiroo Masuoka, Takuya Higashiyama, Mitsuhiro Fukushima, Kaoru Kobayashi, Minoru Kihara, Akihiro Miya
雑誌名: Endocr J. 2014;61(8):821-4. Epub 2014 May 27.
Abstract/Text Differentiated thyroid carcinomas (DTCs) are generally indolent, but few therapeutic strategies are available after a metastatic recurrence that is refractory to radioactive iodine (RAI) therapy. Molecular-target therapy has shown promising results for DTCs with RAI-refractory recurrence. However, not all RAI-refractory recurrences are progressive, and even those that are progressive may not be immediately life-threatening. Here we investigated the prognosis and prognostic factors of 74 DTC patients (52 females, 22 males) in whom RAI-refractory metastases appeared. The five-year and 10-year cause-specific survival (CSS) rates of the 74 patients (8-82 yrs of age; median age at the detection of metastases, 61 yrs) were 95% and 70%, respectively, and the older patients (≥ 60 yrs, n=38) and male patients were significantly more likely to die of carcinoma. Also in multivariate analysis, older age (≥ 60 years) and male gender were independent predictors of carcinoma-related death. Taken together, our data indicate that RAI-refractory metastases of older patients and male patients are more progressive than those of other patients. Further studies are necessary to clarify the appropriate indications for molecular-target therapy for RAI-refractory and progressive metastases.

PMID 24871888  Endocr J. 2014;61(8):821-4. Epub 2014 May 27.
著者: Yasuhiro Ito, Shinichi Suzuki, Ken-Ichi Ito, Tsuneo Imai, Takahiro Okamoto, Hiroya Kitano, Iwao Sugitani, Kiminori Sugino, Hidemitsu Tsutsui, Hisato Hara, Akira Yoshida, Kazuo Shimizu
雑誌名: Endocr J. 2016 Jul 30;63(7):597-602. doi: 10.1507/endocrj.EJ16-0064. Epub 2016 May 20.
Abstract/Text Differentiated thyroid carcinoma (DTC) is generally indolent in nature and, even though it metastasizes to distant organs, the prognosis is normally excellent. In contrast, the overall survival (OS) of patients with radioactive iodine (RAI)-refractory and progressive metastases is dire, because no effective therapies have been available to control the metastatic lesions. However, recently, administration of tyrosine-kinase inhibitors (TKIs) has become a new line of therapy for RAI-refractory and progressive metastases. Previous studies have reported significant improvement regarding the progression-free survival rates of patients with metastatic lesions. However, TKIs cause various severe adverse events (AEs) that damage patients' quality of life and can even be life-threatening. Additionally, metastatic lesions may progress significantly after stopping TKI therapy. Therefore, it is difficult to determine who is a candidate for TKI therapy, as well as how and when physicians start and stop the therapy. The present review, created by Committee of pharmacological therapy for thyroid cancer of the Japanese Society of Thyroid Surgery (JSTS) and the Japan Association of Endocrine Surgeons (JAES) describes how to appropriately use TKIs by describing what we do and do not know about treatment using TKIs.

PMID 27210070  Endocr J. 2016 Jul 30;63(7):597-602. doi: 10.1507/endoc・・・
著者: Hyeong Sik Ahn, Hyun Jung Kim, H Gilbert Welch
雑誌名: N Engl J Med. 2014 Nov 6;371(19):1765-7. doi: 10.1056/NEJMp1409841.
Abstract/Text
PMID 25372084  N Engl J Med. 2014 Nov 6;371(19):1765-7. doi: 10.1056/N・・・

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