The Estimated Number of Prevalent Cases of Thyroid Cancer in Fukushima Prefecture: Unofficial English Translation

Below is an unofficial translation of a document submitted by Dr. Shoichiro Tsugane from the National Cancer Center during the fourth session of the Thyroid Examination Assessment Subcommittee of the Prefectural Oversight Committee Meeting for the Fukushima Health Management Survey, held on November 11, 2014. The document outlined the estimated prevalence (or, more precisely, the estimated number of prevalent cases) of pediatric thyroid cancer in Fukushima Prefecture, calculated by Dr. Kota Katanoda, a staff member for National Cancer Center. This was also published here.

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The Estimated Number of Prevalent Cases of Thyroid Cancer in Fukushima Prefecture

Shoichiro Tsugane (National Cancer Center)

November 11, 2014

Background

During the second session of “Thyroid Examination Assessment Subcommittee” held on March 2, 2014, I commented on a few points regarding evaluation of frequency of thyroid cancer diagnosis as part of the thyroid examination, especially the inappropriateness of comparison with incidence rate data (refer to the handout 4). Considering that frequency of diagnosis during a cross-sectional examination could reflect early diagnosis of thyroid cancer cases which would be clinically diagnosed in the future, it seemed more appropriate to try to compare with the number of thyroid cancer cases estimated with cumulative incidence risk based on incidence data. I requested the calculations be done by the Division of Surveillance (person in charge: Kota Katanoda, Section Head of the Epidemiology and Statistics Section), Center for Cancer Control and Information Services at National Cancer Center.

Methods and Results

See attachment below, The estimated number of prevalent cases of thyroid cancer in Fukushima Prefecture.

Discussion

• As the participation rate in the thyroid examination is 80%, it is necessary to consider the number of cases in the screened population to be about 80% of the estimate.
• Based on cancer incidence rate from 2001 to 2010 (national estimates), the number of thyroid cancer cases clinically diagnosed by age 18 in Fukushima Prefecture will be 2.1 (male 0.5, female 1.6). In the screened population, the estimate will be 1.7 (male 0.4, female 1.3). (An accurate estimate will require the number of screening participants by age). If all of the 104 (male 36, female 68) cases confirmed or suspicious of malignancy  were to be diagnosed with thyroid cancer, the occurrence would be 61 times (male 90, female 52) the estimated number of thyroid cancer cases.
• Assuming there would be no more thyroid cancer cases detected in the screened population in the future (i.e. all future potential thyroid cancer cases were already detected), this screening has detected all the cases of thyroid cancer to be clinically diagnosed by age 35 (age when the number of diagnosed cases will exceed 100). Most of them are estimated to be diagnosed after age 20.
• According to the mortality statistics from the 2011 demographics, probability of dying from thyroid cancer before age 40 (cumulative mortality risk) is 0.00036% (3.6 in 1,000,000) for male and 0.00032%  (3.2 in 1,000,000) for female. That is, about 1 in 300,000 of the screening participants. Thus, it is an extremely rare event to die from thyroid cancer even in the absence of early detection due to screening.
• The current situation in Fukushima Prefecture where over 100 cases of thyroid cancer have been diagnosed in those aged 18 or younger is thought to be due to either excess occurrence due to some cause or diagnosis of many (latent) cancers which could not be clinically diagnosed in the future or which might not be fatal (i.e. overdiagnosis). This is difficult to interpret solely on the basis of an additional cases from early diagnosis of thyroid cancer which might be clinically diagnosed one to several years later (i.e. screening effect).  Also, the number of thyroid cancer cases which could avoid death due to early diagnosis would be at most one.
• In regards to excess occurrence, unlike in the case of acute infection, it is known that a certain number of years is required for a causative factor to lead to carcinogenesis. Thus it is difficult to interpret that the occurrence rate of thyroid cancer diagnosed up to 2014 was increased due to some factor added after the 2011 accident.
• Meanwhile, there is sufficient probability of overdiagnosis as has definitely been observed in adult thyroid cancer, and also there is a precedence of neuroblastoma mass screening in children (refer to handout from the second session). A scenario (note: shown in the graph below) is anticipated where many of thyroid cancer currently diagnosed would either grow very slowly, remain the same in size, or begin to shrink.

Note: modified from Welch and Black, shown below.  Two additional captions are inserted for the vertical axis: 1) “Screening with high sensitivity” immediately above “Abnormal cell” and 2) “Detectable with screening” further above.

(A modified version of Figure 1 from Welch and Black).

Conclusion

This thyroid screening examination was implemented with good intentions on the assumption that “More testing brings more comfort,” and “Early diagnosis is good and causes no harm.” However, it is necessary to share a common understanding that screening with high precision/sensitivity conducted in asymptomatic, healthy individuals could bring about many detriments such as overdiagnosis and related treatments and complications, as well as physical and emotional burden as a consequence of the reduced QOL, the confirmatory examination necessitated by false-positive results, and the primary examination itself.

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Attachment

The Estimated Number of Prevalent Cases of Thyroid Cancer  in Fukushima Prefecture in 2010

November 4, 2014

Division of Surveillance

Center for Cancer Control and Information Services

National Cancer Center, Japan

(1) Data utilized

1. National estimates of thyroid cancer incidence (2001 to 2010)

National estimates of cancer incidence based on cancer registries in Japan (Number of thyroid cancer incidence by sex and age, in 5-year age groups)
ganjoho.jp/data/en/professional/statistics/files/cancer_incidence(1975-2010)E.xls

2. National population (2001-2010)

Population estimates by Ministry of Internal Affairs and Communications (National Census population used for National Census years) (Population by age, sex, in 5-year age groups)
ganjoho.jp/data/en/professional/statistics/files/cancer_incidence(1975-2010)E.xls

3. National mortality from all causes (2001-2010)

Vital statistics (Mortality from all causes by sex, age, in 5-year age groups)
[Volume 3]  General mortality Table 1-1 Deaths by causes (the list of three-character categories), sex and age.
http://www.e-stat.go.jp/SG1/estat/eStatTopPortalE.do

4. Age 0 population in Fukushima Prefecture (1970-2010)

Population for each year of age estimated using the birth cohort method from the census population determined every 5 years as well as the number of births. (Total population by sex and each year of age. Persons of unknown age distributed proportionally).
ganjoho.jp/data/professional/statistics/statistics05/files/07_all_1970-2015.csv

(2) Method of estimation

Cumulative incidence risk* of thyroid cancer for each year of age was calculated and multiplied by the yearly age 0 population in Fukushima Prefecture, in order to obtain the number of cumulative incident cases for each year of age. Addition of the obtained number from age 0 to the chosen age will yield a total number of the cumulative incident cases up to the chosen age, which is regarded as the number of prevalent cases. Details are shown in steps ①～③.

*Cumulative incidence risk: probability of developing a certain disease by a certain age

① Calculation of cumulative incidence risk of thyroid cancer (for 5-year age groups) (Figure 1)

Using items 1-3 in section (1), cumulative incidence risk of thyroid cancer by 5-year age groups is calculated. Population consisting of 100 persons of age 0 is assumed, and cumulative incidence risk is determined by counting the number of cancer incidence that occurred after aging the population by 5 years and subtracting the number of deaths (from all causes).  (Lifetime Data Anal. 4: 169-186, 1998)

② Calculation of cumulative incidence risk of thyroid cancer (for each specific year of age)

Spline function is applied to the cumulative incidence risk of thyroid cancer for 5-year age groups, calculated in section ①, to estimate the cumulative incidence risk for each specific year of age.

③ Calculation of the number of thyroid cancer cases

The cumulative incidence risk of thyroid cancer for 5-year age groups, calculated in section ①, is multiplied by the respective yearly age 0 population in Fukushima Prefecture from (1)-4 (age 0 population in 2010 x risk at age 0, age 0 population in 2009 x risk at age 1, and so on), to calculate the number of cumulative incidence at each age. Total of the number of cumulative incidence from age 0 to 18 is regarded as the number of thyroid cancer cases up to age 18.

(3) Results (Figure 2)

The number of thyroid cancer cases for ages 18 and younger in Fukushima Prefecture as of 2010 was estimated to be 2.0 (male 0.5, female 1.6). It was estimated that the number of cases of both male and female will exceed 50 at age 31, and 100 at age 35. 

(4) Points to consider

• As thyroid cancer incidence rate below age 20 is low, 10-year average data was used from 2001 to 2010. However, as thyroid cancer incidence rate is showing a tendency for long-term increase, 10-year average incidence rate might be underestimation compared to the current incidence rate.
• The methodology used in this estimation assumes 10-year incidence by age group from 2001 to 2010 is experienced by all generations up to age 40 as of 2010. Along with the fact the incidence rate is showing a tendency for long-term increase, this assumption might overestimate incidence rate as the age increases.
• Spline function was used in calculation of cumulative incidence risk at each year of age here, but another method might be used in (2)-① where the population is aged by 1 year (instead of 5 years).
• As thyroid cancer incidence below age 20 is low, national estimates using population-based cancer registry data might be unstable.
• Although national estimates of cancer incidence were based on population-based cancer registries fulfilling a certain quality standards, some degree of incompleteness in registrations might have led to underestimation.

End

Figure 1  Estimated cumulative incidence risk for thyroid cancer

Figure 2  Estimated cumulative prevalence of thyroid cancer in Fukushima Prefecture in 2010.

http://static.www.bmj.com/sites/default/files/response_attachments/2014/12/_figure%2Blegend.pdf

Acknowledgement: Drs. Tsugane and Katanoda graciously accommodated my request for proofreading to assure accuracy of the translation, especially the technical terms and expressions.

May 2015 Interim Summary Regarding Thyroid Examination: Unofficial English Translation

At the 19th Prefectural Oversight Committee Meeting for the Fukushima Health Management Survey held on May 18, 2015, an Interim Summary was submitted by the Thyroid Examination Assessment Subcommittee. Although it is called the "Interim Summary," this is essentially the final report by this particular subcommittee. As is customary with Japanese governmental committees, the end of the fiscal year calls for the submission of a summary report, often followed by the prearranged dissolution of the committee.

Below is a complete, unofficial English translation of the Interim Summary. (It has been checked by one of the officials for accuracy).

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The 19th Prefectural Oversight Committee Meeting for the Fukushima Health Management Survey (May 18, 2015)

Interim Summary Regarding Thyroid Examination

Thyroid Examination Assessment Subcommittee, Prefectural Oversight Committee Meeting for Fukushima Health Management Survey, March 2015

The Thyroid Examination Assessment Subcommittee of the Prefectural Oversight Committee Meeting for the Fukushima Health Management Survey was established at the 12th Prefectural Oversight Committee Meeting for Fukushima Health Management Survey held on August 20, 2013. There it was decided to establish a subcommittee specific to the thyroid examination within the Oversight Committee in order to verify and evaluate methods and results of the examination and to disseminate information to Fukushima residents. The first session of the Subcommittee convened on November 27, 2013.

The Subcommittee has deliberated the validity of the scientific, medical and ethical basis for the examination results and their analysis, the administrative responses, the follow-up survey, and the mental care for the residents, from the standpoint of the examination, which is drawing a high interest from the international community. Below is the summary of discussions by the Subcommittee:

1. Assessment of the examination results, responses, and treatment from Initial Screening

Initial Screening (first-round screening) beginning in October 2011 targeted approximately 300,000 Fukushima residents who were 18 or younger at the time of the accident. So far 112 have been diagnosed with thyroid tumors which are “malignant or suspicious for malignancy” as a result of FNAB (fine-needle aspiration biopsy). 99 have been operated on, leading to confirmed diagnosis of 95 cases of papillary thyroid cancer, 3 cases of poorly differentiated thyroid cancer, and 1 benign nodule (data as of March 31, 2015).

The number of cancer cases in the examination result is several tens of times larger than the number of patients estimated from incidence statistics of thyroid cancer analyzed in the regional cancer registry in Japan. This may be interpreted as the result of either excessive occurrence due to radiation exposure or over-diagnosis (i.e. diagnosis of cancer which is neither life-threatening nor symptomatic). There were opinions that, based on scientific knowledge up to know, the possibility of the former (excess occurrence) could not be denied completely, but it was more likely to be the latter (over-diagnosis).

On the other hand, there was an opinion that even if the increase was due to over-diagnosis, if it weren’t for the early diagnosis and treatment there was a possibility for the majority of cases to become symptomatic or life-threatening cancer in several years or even later. 

In addition, if it were papillary thyroid cancer, its biological features would allow for an option of regular follow-up without treatment. Risk assessment of diagnosis and treatment of papillary thyroid cancer detected during screening, including surgical indications, should be left to specialists.

※ Current diagnosis and treatment are based on the clinical guidelines of the Japan Society of Thyroid Surgery. However, there was an opinion calling for a separate clinical guideline appropriate for the current situation in Fukushima or for the pediatric thyroid cancer because the screening is being conducted in asymptomatic individuals and also the prognosis of papillary thyroid cancer is much better in children than in adults.

※ A concurrent improvement in cancer registry was suggested so that all cases of thyroid cancer are recorded. 

2. Assessment of radiation effects

At present it is not possible to conclude whether thyroid cancer cases detected during screening are radiogenic. According to Initial Screening which was completed, thyroid cancer cases detected so far are considered unlikely to be due to radiation effects because of two reasons: 1) exposure dose is much less than in Chernobyl, and 2) no cancer cases have been detected in those who were aged five or younger at the time of the accident. Nevertheless, a long-term, continuing study is essential in order to assess the effects of radiation exposure.

In addition, information on internal exposure dose from radioactive iodine in the early post-accident period is extremely important in determining the effect of the accident. Thus coordination with such dose assessment studies should always be included in advancing the thyroid examination.

On the assumption thyroid cancer might occur due to radiation exposure in the future, it is necessary at this time to consider in advance how to  quantify the size of effect that can be confirmed and the type of data or analysis that could be used to confirm it.

3. Covering medical expenses with government funds

It is difficult to identify the cause of individual thyroid cancer cases. However, as a group, many patients undergoing confirmatory examination end up receiving the medical care they would not have had to receive, at least for the time being (or perhaps in lifetime), if it weren’t for the screening. Thus, if they end up receiving regular medical care with insurance due to their participating in screening, at this time it is desirable for the government to cover their medical expenses incurred after the confirmatory examination.

4. Follow up of the eligible subjects

It is critical to conduct a follow-up survey of the subjects eligible for thyroid examination, especially those who were infants and toddlers at the time of the accident, in order to assess the occurrence and the prognosis of thyroid cancer. 

Also, it is important to thoroughly consider how to follow the age group that will increasingly move out of Fukushima Prefecture (such as to attend college and work). This is an important point in an epidemiological follow-up study.

5. Disclosure of examination results

The establishment of a re-evaluation system is suggested where the anonymous examination results are re-evaluated with transparency by a team including many researchers.

This re-evaluation should be accompanied by careful consideration of privacy protection. 

6. Future thyroid examinations

The nuclear power plant accident brought to Fukushima residents not only “unnecessary exposure” but also the risk burden of “potentially unneeded diagnosis and treatment of thyroid cancer.” However, in regards to the thyroid examination, it is necessary to consider the following points: the possibility cannot be denied that future thyroid cancer occurrence might be due to radiation exposure from the accident; the wishes of many residents to undergo the examination in order to relieve anxiety; and the need for an epidemiological assessment into the existence of the increased occurrence of thyroid cancer due to the effects of the accident, for the purpose of informing residents as well as domestic and international communities. 

Thus, the current thyroid examination should be continued, with a conditional policy to obtain consent of the residents. It should be continued within the examination structure allowing the assessment of the presence or absence of an increased occurrence of radiation-induced thyroid cancer. Also the residents should receive an easily comprehensible explanation that: there may be detriments as well as benefits to examination; and that (papillary) thyroid cancer is the type of cancer whose initial presentation at the time of detection may not necessarily progress to a life-threatening condition (i.e. it has a good prognosis). 

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2015 Update: Details of Fukushima Thyroid Cancer Surgical Cases

This post contains a translation of the first three abstracts presented at the Symposium 1 "Diagnosis and Treatment of Childhood and Adolescent Thyroid Cancer" during the 27th Annual Congress of the Japan Association of Endocrine Surgeons held on May 28-29, 2015, in Fukushima City.

Shinichi Suzuki, a thyroid surgeon at Fukushima Medical University and director of Thyroid Ultrasound Examination, was the program chair. (See his greeting here in Japanese).

Background on lack of information disclosure and Suzuki's stance

On May 18, 2015, only 10 days before the Annual Congress of the Japan Association of Endocrine Surgeons, the Nineteenth Oversight Committee for Fukushima Health Management Survey convened, where Suzuki's unexpected absence surprised journalists and audience on site as well as on the Internet. Suzuki's potential absence from the Oversight Committee was not mentioned at the previous Oversight Committee session on February 12, 2015. Masafumi Abe, vice president of Fukushima Medical University, explained during the press conference that Suzuki would be focusing on clinical aspects of Thyroid Ultrasound Examination--namely, surgery and training of medical personnel. Having been involved with the Thyroid Ultrasound Examination from the planning stage, for the past four years, Suzuki has been doing double duty running the program and conducting surgeries. It was decided that Suzuki would hand over the day-to-day operation of Thyroid Ultrasound Examination to Akira Ohtsuru, an internist who was dispatched from Nagasaki University to become a professor at the Department of Radiation Health Management at Fukushima Medical University. (By the way, although it is not clearly stated in Japanese sites, Shunichi Yamashita still presides over Thyroid Ultrasound Examination as Senior Director according to this site).

Even though Suzuki never willingly shared clinical details of the thyroid cancer cases at either the Oversight Committee or the Thyroid Examination Assessment Subcommittee, he was at least quite knowledgeable about the results being presented, eloquently reading aloud the printed results with almost a salesman's pitch. The reason clinical details have not been openly shared is because, during the confirmatory examination, from the point of the fine-needle aspiration cytology (FNAC) on, the medical care of the patients technically leaves the Fukushima Health Management Survey, shifting from "screening" covered by a special prefectural budget to "regular medical care" utilizing the national health insurance. This meant a stricter layer of protection for patient privacy. In addition, there was no comprehensive data collection system organized by any one entity, and no one had data compiled of all the surgical cases, given the small number of patients operated at facilities other than Fukushima Medical University.

To his credit, during the Sixteenth Oversight Committee meeting held on August 24, 2014, Suzuki asked the Committee to discuss and decide which information needed to be disclosed and how the information would be handled so that his team could decide which clinical information would be released. On one hand, he appeared genuinely concerned about the handling of medical information, but on the other hand, it seemed as if he were trying to release as little information as he could get away with. In the past, Fukushima Medical University refused repeated requests from committee members and journalists to release details of demographic data on the cancer cases, which might offer a glimpse into exposure doses of individual cases, 

Given the above circumstance, it was a shock when news articles reported that Suzuki released detailed information on surgical cases, only 4 days later, at the 52nd Annual Meeting of Japan Society of Clinical Oncology held during August 28-30, 2014. He reported an updated version of this detailed information on surgical cases at the November 11, 2014 Thyroid Examination Assessment Subcommittee meeting, only after Fukushima Prefecture requested it. An even more updated version of information on surgical cases is what was presented at an endocrine surgeons' meeting on May 28, 2015, as translated below. 

Incidentally, Suzuki caused quite a stir at the November 11, 2014, Thyroid Examination Assessment Subcommittee meeting when he stated his intention to present results of the genetic testing at the Japan Thyroid Association meeting to be held several days later. Subcommittee members were not pleased and asked Suzuki to present the abstract of the upcoming presentation, which is in the public domain, but Suzuki declined stating the abstract belonged to the Japan Thyroid Association and he could not release any information unless the Subcommittee could provide an official procedure or guideline for information release on the spot.  

The screening portion of Thyroid Ultrasound Examination is managed by the government of Fukushima Prefecture, which in turn commissions the work to Fukushima Medical University. However, when the cases enter the stream of regular medical care, how the data is utilized in research appears to be beyond the grasp of Fukushima Prefecture. Suzuki says the research is approved by the Ethics Committee of Fukushima Medical University and consent forms have been signed by the patients. 

What is clear is that Fukushima Medical University is prioritizing academic achievements over sharing of information with the very people the information belongs to--Fukushima residents. A prefectural official stated during the press conference after the Fourth Session of Thyroid Examination Assessment Subcommittee that the data itself belonged to Fukushima residents. He continued to state that although he understood the data might be processed and analyzed for publication or presentation at academic conferences and it might not be possible for it to be publicized beforehand, he would like at least the original "raw" data to be shared with Fukushima Prefecture residents at committee meetings.

Even as of now, it seems that no clear procedure has been set regarding sharing of data with Fukushima residents. The Oversight Committee should be where such procedures are developed, yet recent sessions have not attempted it.

Since he is no longer attending the Oversight Committee, and the Thyroid Examination Assessment Subcommittee essentially finished its course as of March 2015 with no future meetings scheduled, Suzuki will not have an opportunity to present detailed information on surgical cases to the public or be held accountable for prioritizing academic meetings when disclosing information. His successor, Ohtsuru, did a less than adequate job of verbally presenting printed results, barely able to answer questions from committee members and journalists. To the journalists who were hoping to push for disclosure of not just surgical details but demographic details of cancer cases, this seemed like backtracking.

The abstracts translated below do not by any means offer comprehensive analyses up to date with the most current results of Thyroid Ultrasound Examination. However, they do present findings and analyses of some of the cases detected during the Initial Screening. This presentation by Kenneth Nollet at the 62nd session of UNSCEAR held during June 1-2, 2015, in Vienna, Austria, includes an easy-to understand overview of Thyroid Ultrasound Screening program and its most recent results reported on May 18, 2015. (Some expressions in this presentation might be disputable, such as calling "A2" as "normal thyroids"). Nollet is Director of the Department of International Cooperation, Radiation Medical Science Center for the Fukushima Health Management Survey at Fukushima Medical University.

Recap of the most recent results of FNAC from Initial Screening as of March 31, 2015, reported on May 18, 2015

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27th Annual Congress of the Japan Association of Endocrine Surgeons

Symposium 1 "Diagnosis and Treatment of Childhood and Adolescent Thyroid Cancer" 

SY1-1 “Cytological and Tissue Diagnosis in Pediatric and Adolescent Thyroid Cancer”

Atsuhiko Sakamoto

Department of Pathology and Laboratory Medicine

Omori Red Cross Hospital

Fine-needle aspiration cytology is highly regarded as a method to confirm diagnosis before starting treatment of thyroid lesions such as tumor. Tissue diagnosis plays a role of confirmatory diagnosis (final diagnosis) in the examination of surgical specimen.

While pediatric and adolescent thyroid cancer has been considered rare in general, it attracted attention due to its high incidence as radiation-induced cancer after the Chernobyl accident. It drew interest in Japan after the Fukushima Daiichi nuclear power plant accident due to the Great East Japan earthquake and tsunami, and thyroid examination was started in Fukushima residents 18 or younger at the time of the accident, as part of the Fukushima Health Management Survey. I am involved with the cytological assessment and tissue diagnosis as a member of the Diagnostic Criteria Inquiry Subcommittee of the Thyroid Examination Expert Committee at Fukushima Medical University. From that standpoint, I would like to show during this session general characteristics of pediatric and adolescent thyroid cancer in terms of cytological and tissue diagnosis, along with the results from evaluation of radiation exposure cases in the Fukushima Health Management Survey.

Papillary thyroid cancer is the most common subtype of primary thyroid cancer. Papillary thyroid cancer occurs in high frequency, more than 50%, in both adult and pediatric/adolescent cases. Papillary thyroid cancer has many variants other than the classical type. According to the Sixth Edition of Thyroid Cancer Management Guideline (2005), based on the WHO Classification of Tumours (2004), special subtypes of papillary thyroid cancer can be divided into: 1) follicular, 2) encapsulated, 3) macrofollicular, 4) oxyphilic cell type, 5) diffuse sclerosing, 6) tall cell, and 7) cribriform-morular variants.

According to the tally by the Fukushima Health Management Survey, there were 84 cases (96.6%) of papillary thyroid cancer amongst 87 surgical cases of pediatric and adolescent thyroid cancer at the end of 2014. They included 3 cases of follicular variants and 4 cases of cribriform-morular type. The solid variant, seen in high frequency after the Chernobyl accident, is classified as poorly differentiated thyroid cancer in the Sixth Edition of Thyroid Cancer Management Guideline.

The Fukushima data include many small-size cancers, offering big hints for the elucidation of the behavior of microcarcinoma and for clinical management consideration.

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SY1-2 “Genetic Mutations in Pediatric and Adolescent Thyroid Cancer”

¹Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University; ²Department of Global Health, Medicine and Welfare, Atomic Bomb Disease Institute, Nagasaki University; ³Department of Radiation Molecular Epidemiology, Atomic Bomb Disease Institute, Nagasaki University; ⁴Department of Thyroid and Endocrinology, School of Medicine, Fukushima Medical University

Norisato Mitsutake¹, Michiko Matsuse¹, Tatiana Rogounovitch², Vladimir Saenko³, Toshihiko Fukushima⁴, Shinichi Suzuki⁴, Shunichi Yamashita¹

An increasing number of patients are diagnosed with asymptomatic pediatric/adolescent thyroid cancer due to a dramatic advancement of diagnostic ultrasound technology as well as an increase in thyroid ultrasound examinations in pediatric and adolescent populations. For the purpose of elucidating biological characteristics of these cancers, analysis and assessment were conducted on the relationship between the known oncogene mutations and the clinico-pathological findings reported in papillary thyroid cancer so far. Subjects were 65 surgical cases of pediatric and adolescent papillary thyroid cancer: 22 males and 43 females; average age 17.4 years; 59 cases of classic subtype, 2 cases of follicular variant, and 4 cases of cribriform-morular type. Oncogene mutations investigated and the number of cases in each type of mutation are as follows: BRAFV600E mutation — 42 cases (64.6%); RAS mutation (including NRAS, KRAS and HRAS) — 0 case; RET/PTC1 — 5 cases (7.7%); RET/PTC3 — 1 case (1.5%); ETV6/NTRK3 — 4 cases (6.2%); AKAP9/BRAF — 0 case; and TERT promoter mutation — 0 case. Cases with BRAFV600E mutation were characterized by significantly older age and smaller tumor diameter compared to other cases. The pattern of these oncogene mutations was nearly identical to the pattern seen in adults, except for the TERT promoter mutation, observed in approximately 10% of adults (usually only in cases aged 45 and older, and in highly correlation with age), which was not at all observed in these subjects. This is considered to be extremely important information in mechanistic considerations of the carcinogenesis and development of thyroid cancer in human.

(Note: Even though the cases presented here are not specified as being from Fukushima Thyroid Ultrasound Examination, similarities of data to the previous presentation on genetic testing results suggest most of them are indeed from the Fukushima data).

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SY1-3 “Facts about the Pediatric Thyroid Cancer Treatment in Fukushima Prefecture”

¹Department of Thyroid and Endocrinology, School of Medicine, Fukushima Medical University, ²Department of Organ Regulatory Surgery, Fukushima Medical University, ³Department of Laboratory Medicine, Fukushima Medical University

Izumi Nakamura¹, Shinichi Suzuki¹, Yudai Hirata¹, Takahiro Nakajima¹, Nobuhiro Hoshi², Yuko Murakami², Hirokazu Okayama², Chiyo Ohkouchi¹, Satoshi Suzuki¹, Keiichi Nakano¹, Hiroshi Mizunuma¹, Toshihiko Fukushima¹, Satoshi Suzuki¹, Hiroki Shimura³, Seiichi Takenoshita²

Introduction

Even now when four years have passed since the Fukushima disaster, the thyroid ultrasound examination quietly continues as part of the Fukushima Health Management Survey in Fukushima Prefecture. We report here some facts about the post-accident pediatric thyroid cancer treatment in Fukushima up to October 31, 2014.

Subjects

109 of the confirmatory examination participants in the thyroid ultrasound examination, conducted as part of the Fukushima Health Management Survey, were diagnosed with suspicious or confirmed malignancy, and 85 of them had surgeries. We discuss 79 of the 80 cases operated on at Fukushima Medical University, excluding the single case which was post-operatively diagnosed as benign nodules. Pathological diagnosis confirmed 76 cases as papillary thyroid cancer and 3 as poorly-differentiated thyroid cancer.

Results

Of 79 cases, pre-operative diagnosis showed 25 cases (32%) had tumor diameter ≤ 10 mm, including 13 (16%) cases classified as cT1acN0cM0 [i.e. no lymph node or distant metastasis]. Surgery was indicated in 10 of these 13 cases as they were suspected to be close to the trachea or the recurrent laryngeal nerve, or have extrathyroidal extension. The remaining 3 cases were operated on due to wishes of patients and/or families, despite discussion on the possibility of non-surgical follow-up. Pre-operatively, 25 cases (31%) were positive for lymph node metastasis, and 3 cases (4%) were suspected to have lung metastasis. Surgical methods included total thyroidectomy in 6 cases (8%) and hemithyroidectomy in 73 cases (92%). Lymph node dissection was conducted in all cases, with 82% limited to the central compartment and 18% including the central and lateral compartments. Post-operative pathological diagnosis revealed 17 cases (22%) with tumor diameter ≤ 10 mm, and 44% with extrathyroidal extension, pEx1*, and 75% with lymph node metastasis. No post-operative complications (post-operative hemorrhage, permanent paralysis of recurrent laryngeal nerve, hypothyroidism in cases other than total thyoidectomy cases, and hypoparathyroidism) were observed.

Conclusion

We reported the current situation of pediatric thyroid cancer treatment in Fukushima. Treatment of pediatric thyroid cancer calls for consensus-building, and we expect findings in Fukushima will become useful in revising guidelines in the future.

*Note: Ex1, a designation defined in Japan's unique guideline, "The Sixth Edition of Thyroid Cancer Management Guideline," is considered to be equivalent to T3 in the TNM classification. The following is translation of the information on thyroid cancer classification from the National Cancer Center.

• T3: Tumor greater than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues)
• Ex1: Minimal extrathyroid extension limited to sternothyroid muscle or adipose tissues. (Note: Cases with adhesion to organs other than sternothyroid muscle or adipose tissues which can be detached using a sharp instrument are considered Ex1). 

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Some comparisons with the previous report on surgical cases:

The third abstract above includes information based on Thyroid Ultrasound Examination results as of October 31, 2014, reported at the meeting of the Seventeenth Oversight Committee for Fukushima Health Management Survey held on December 25, 2014. It is an updated version of the report, "Regarding the Surgically Indicated Cases" submitted by Suzuki to the fourth session of Thyroid Examination Assessment Subcommittee on November 11, 2014 (see Section 1 of this post), adding detailed information for 25 more cases which underwent surgery during the four-month period between July 1, 2014 and October 31, 2014.

Of these 25 additional surgical cases, 24 were papillary thyroid cancer and 1 was poorly differentiated thyroid cancer. Compared with the June 30 data, the number of cases with a pre-operative tumor diameter ≤ 10 mm increased by 13 from 12 (22%) to 25 (32%), while the number of cases with a post-operative tumor diameter ≤ 10 mm only increased by 2 from 15 (28%) to 17 (22%). This means that 13 of the 25 additional cases had a pre-operative tumor diameter ≤ 10 mm, but 11 of those 13 cases were actually larger than 10.1 mm post-operatively. 10 of the 13 cases were operated on because they were close to the trachea or the recurrent laryngeal nerve or because the tumor extended outside the thyroid gland into the surrounding tissues or organs. (By the way, it has never been clarified whether any of the patients had any subjective symptoms at examination).
Proportions of pre-operatively diagnosed lymph node metastasis and lung metastasis remained the same at 31% and 4%, respectively. Of the 25 additional cases, only one underwent total thyroidectomy and the remaining 24 had hemithyroidectomy which leaves a half of the thyroid gland intact to produce thyroid hormones.

The proportion of those receiving lymph node dissection limited to the central compartment increased from 63% to 82%, while lymph node dissection extending to the lateral compartment was performed in 18%, down from 33%. (Without further information available, it is not clear why these proportions changed).

In the post-operative diagnosis, the proportion of cases with extrathyroidal extension, pEx1, slightly increased from 37% to 44%, while the lymph node metastasis was seen in 75%, about the same as 74% reported previously. 

Based on the above information, it appears that the operated cases meet the indications for surgery by the Japanese guidelines.