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Friday, January 6, 2017

Fukushima Thyroid Examination December 2016: 145 Thyroid Cancer Cases Confirmed (101 in the First Round and 44 in the Second Round)

145 Thyroid cancer cases confirmed in Fukushima as of September 30, 2016--101 in the first round and 44 in the second round (Total of 183 cases including suspected cancer cases--115 in the first round and 68 in the second round).

On December 27, 2016, the 25th Oversight Committee for Fukushima Health Management Survey convened in Fukushima City, Fukushima Prefecture. Among other information, the Oversight Committee released the latest results (as of September 30, 2016) of the second and third rounds of the Thyroid Ultrasound Examination (TUE). Official English translation of the results is posted here. The narrative below presents basic facts from the new data in perspective, including information covered during the committee meeting and the subsequent press conference.

Overview
As of September 30, 2016, there are 9 more cases with cancer or suspicion of cancer from the second round, making a grand total of 183 (184 including the single case of post-surgically confirmed benign nodule) for the first and second round results combined. The number of surgically confirmed cancer cases, excluding the aforementioned case of benign nodule, increased by 10 to 145 (101 from the first round and 44 from the second round), and the remaining 38 (14 from the first round and 24 from the second round) await surgical confirmation. 

Although the final reporting of the second round screening results was widely anticipated at this Oversight Committee meeting, it was revealed that the confirmatory examination was still ongoing and the results were incomplete. 

Since the last results were released, 10 additional cases from the second round have been operated on. All 10 cases were confirmed as papillary thyroid cancer during the post-surgical pathological examination of the resected thyroid gland tissue. 

The second round screening (the first Full-Scale screening) was originally scheduled to be conducted from April 2014 through March 2016, and the primary examination (with the participation rate of 70.9% and the progress rate of 100.0%), is essentially complete. But the confirmatory examination (with the participation rate of 75.8% and the progress rate of 92.2%) is still ongoing apparently due to a schedule backlog in local hospitals in cities far from Fukushima Medical University, such as Iwaki City. 

Conducted every 2 years up to age 20, the TUE transitions to milestone screenings to be conducted every 5 years beginning at age 25. Some residents are beginning to participate in the milestone screening at age 25, and if they have never participated in TUE, the results will be added to the second round screening results. Thus the number of the second round screening participants is expected to increase even though the screening period technically ended in March 2016.

Meanwhile, the third round screening (the second Full-Scale Screening) which began on May 1, 2016, is scheduled to run through March 2018--the end of Fiscal Year 2018. As of September 30, 2016, 49,387 have participated in the primary examination out of the survey population of 336,609 residents, at the participation rate of 14.7%. So far 211 have been determined to require the confirmatory examination. Results of the confirmatory examination were not available as it only began on October 1, 2016 and the TUE results released at this Oversight Committee meeting covers data up to September 2016.

In some cases, confirmatory examinations from the second and third rounds might be simultaneously ongoing, or there could be significant delays in conducting confirmatory examinations due to logistical issues such as the lack of manpower. A two-year screening period originally designed for subsequent rounds of the Full-Scale Screening is essentially spread over a longer time period, overlapping with the next round of screening. A precise interpretation of results from each round of screening might be nearly impossible.

Full-Scale Screening (first and second)
To be conducted every 2 years until age 20 and every 5 years after age 20, the Full-Scale screening began with the second round screening (first Full-Scale Screening) in April 2014, including those who were born in the first year after the accident. There are 381,282 eligible individuals born between April 2, 1992 and April 1, 2012. As of September 30, 2016, the participation rate remained the same as 3 months earlier at 70.9% but lower than 81.7% at the first round screening, with 270,454 actually participating in the primary examination. Results of the primary examination have been finalized in 270,431, and 2,222 (increased by 5 since the last Oversight Committee meeting) turned out to require the confirmatory examination. 

The confirmatory examination is still ongoing for the second round. Of 2,222 requiring the confirmatory examination, 1,685 have participated at the participation rate of 75.8% (increased from the previous 66.6% but still lower than 92.8% from the first round screening), and 1,553 have received final results including 189 that underwent fine-needle aspiration cytology (FNAC). FNAC revealed 68 cases suspicious for cancer. Confirmation of thyroid cancer requires pathological examination of the resected thyroid tissue obtained during surgery. As of September 30, 2016, 44 underwent surgery and 43 were confirmed to have papillary thyroid cancer. One remaining case was confirmed to have "other thyroid cancer" according to the classification in the seventh revision of Japan's unique thyroid cancer diagnostic guidelines. A specific diagnosis was not revealed, but Akira Ohtsuru, in charge of the thyroid screening, confirmed that it was neither poorly differentiated thyroid cancer nor medullary cancer. He has previously mentioned it was a differentiated thyroid cancer that is not known to be related to radiation exposure.

The third round screening or the second Full-Scale Screening has covered 49,387 or 14.7% of the survey population of 336,609. The primary examination results have been finalized in 30,253 or 61.3% of the participants, and 211 would require the confirmatory examination. No results from the confirmatory examination were available because it began as of October 1, 2016.

Newly diagnosed cases in the second round
In the second round, 9 cases were newly diagnosed by FNAC with lesions suspicious of cancer. They were 3 females (ages at exposure: 11, 14 and 15) and 6 males (ages at exposure: 7,10, 11, 12, 12 and 16). Their places of residence at exposure (with the number of individuals in parentheses) include FY 2015 target municipalities of Fukushima City (2) and Shirakawa City (1) and FY 2016 target municipalities of Iwaki City (2), Tanakura Town (1) and Kitakata City (3).

The youngest individual newly diagnosed with suspected cancer was age 7 at the time of the accident. The lack of surge in cases in younger patients aged 0-5 at exposure in the first 4-5 years since the Fukushima nuclear accident is regarded by Fukushima Medical University as one of the reasons denying Fukushima thyroid cancer cases being radiation-induced. However, it was after the first 4 years since the Chernobyl accident that thyroid cancer cases in those aged 0-5 at exposure dramatically increased. This underscores the importance of continuing screening to follow the trend in this age group. No determination could be logically made regarding radiation effects based on the lack of patients who were ages 0-5 at the time of the Fukushima accident. (See this for more information).

Prior diagnostic status of the cases newly diagnosed in the second round
Of 68 total cases suspected or confirmed with cancer in the second round, 31 were A1, 31 were A2, and 5 were B in the first round. One remaining case never underwent the first round screening (no information such as age, sex or place or residence, is available regarding this case).

Thirty-one cases that were A1 in the first round by definition had no ultrasound findings of cysts or nodules, whereas 7 of 31 cases that were previously diagnosed as A2 had nodules. with the remaining 24 being cysts. All 5 cases that were previously diagnosed as B were nodules, and at least 2 of them had undergone the confirmatory examination in the first round. 

This means 55 of 68 cases or 81% of the second round cases suspected or confirmed with cancer had no lesions detectable by ultrasound in the first round. It has been speculated by some that these 55 cases were new onset since the first round, suggesting the cancer began to form in 2 to 3 years after the first round screening. This would seem to conflict with the common notion that thyroid cancer in general is slow growing. 

Ohtsuru emphasized that there were no missed diagnosis in the first round. Rather these 55 cases might comprise newly detected lesions that were simply undetectable by ultrasound in the first round. He firmly denied these were newly formed lesions. He also stated it wasn't clear if they were previously invisible, which is the expression he used in earlier meetings. 

Other physicians in the committee, Akihito Horikawa (Futaba County Medical Association president) and Kazuo Shimizu (a thyroid surgeon), concurred with the idea that some lesions might have been simply undetectable even with the use of highly sensitive equipments, although Shimizu did not seem to completely disregard the possibility of new onset lesions. It seemed that the expression of "missed diagnosis" was avoided in honor of considerable efforts made by those actually conducting the ultrasound screening. It is possible some of the ultrasound images are overread at the diagnostic subcommittee with undisclosed members discussing some of the cases in closed meetings, but so far no concrete evidence has been given to confirm such activities.

An issue of the female to male ratio
The female to male ratio of cancer cases warrants a special attention. For thyroid cancer, the female to male ratio is nearly 1:1 in the very young, but it is known to increase with age and decrease with radiation exposure. In the second round, the female to male ratio has been decreasing with successive results. It was 1.36:1 when the results were released in September 2016, and now it is 1.19:1. 

Towards the end of the press conference, Mako Oshidori sharply asked why there has been no evaluation regarding the female to male ratio in the Fukushima thyroid cancer cases. (For the transcript of her question in Japanese, see here). She pointed out that Kazuo Shimizu, a committee member and thyroid surgeon, has asked questions regarding the female to male ratio issue multiple times in the past three and a half years. In fact, Ohtsuru responded to an earlier question by Shimizu during this meeting that the female to male ratio issue is yet to be evaluated by Fukushima Medical University and that the committee meeting was simply a place where results were presented. 

Oshidori chastised Fukushima Medical University for not even trying to compare results with existing outside data and conduct any analysis in all these years. In response, Ohtsuru acknowledged that the female to male ratio is smaller than what is clinically expected but explained they were not sure what is causing it. Oshidori stated there was no scientific paper that showed a decrease in the female to male ratio due to the screening activity. Rather, scientific evidence shows screening activities generally increase the female to male ratio due to more females being diagnosed with thyroid cancer. Ohtsuru replied that it is true that screening activities increased the female to male ratio in adults but it was unclear if the similar trend is expected in children. Furthermore, differences in a screening frequency and screening equipments should be taken into consideration. Oshidori acknowledged there was much to be considered and pressed for the Thyroid Examination Evaluation Subcommittee to be reconvened.

A new third-party committee proposed
At the end of the Oversight Committee meeting, an issue was raised by Chairman Hokuto Hoshi relating to the recommendations received by the Fukushima governor from the 5th International Expert Symposium in Fukushima on Radiation and Health: “Chernobyl+30, Fukushima+5 - Lessons and Solutions for Fukushima’s Thyroid Question." (See this post for more information on the symposium). Hiroyuki Kobayashi, a Fukushima prefectural government official in charge of the Fukushima Health Management Survey, reported that the governor received the recommendations on December 9, 2016. Kobayashi stated that the prefectural government has received opinions and suggestions from various entities and the recommendations by the 5th International Expert Symposium were placed in the same category (as if to explain the recommendations did not have any special status). Kobayashi then asked the committee to discuss the recommendations.

In his monologue, Chairman Hoshi went on to propose an establishment of an "international, third-party, neutral, scientific, up-to-date and evidence-based" expert committee that would discuss issues surrounding the TUE and present information in a manner that would aid the "understanding by Fukushima residents." This proposal appeared to be taken from the item number 4 of the recommendations "to convene the expert working groups on 'Nuclear Disasters and Health Monitoring,' especially focusing on thyroid problems, could provide professional recommendations to the current TUE in Fukushima in the future."

Chairman Hoshi proceeded to have some of the committee members explain how third-party evaluation committees function at the Radiation Effect Research Foundation (RERF) and the National Institute of Radiological Sciences (NIRS). This clearly came as a surprise to those who were asked to make presentations on the spot, creating a slightly uncomfortable atmosphere. 

Multiple questions and opinions ensued during the press conference doubting the necessity and validity of such a new third-party committee when the Oversight Committee's own Thyroid Examination Evaluation Subcommittee, which last met in March 2015 and issued a mid-term report on the first round screening, has not even been reconvened to consider the second round screening results. (At the last Oversight Committee meeting held on September 14, 2016, the FMU officials said the second round screening data would be analyzed when all the second round data is in, and the Oversight Committee itself seemed to be waiting for the completion of the second round rather than holding the subcommittee meetings concurrently).

Regarding the future status of the TUE 
The recommendations by The 5th International Symposium include clauses such as:

"(...) thyroid screening of people who do not have symptoms of possible thyroid disease has the potential to do more harm than good to the population, and should only be carried out, when clear benefits to the population can be defined."

"Participation in the health surveys and the thyroid screening program should be voluntary."

It should be noted that the recommendations did not consider opinions by Chernobyl researchers such as Yuri Demidchik from Belarus, Tetiana Bogdanova from Ukraine and Pavel Rumiantsev from Russia, whose presentations at the symposium made clear that thyroid ultrasound screening is beneficial, since their names are not included in the list of invited experts who were consulted.

For record, participation in the health surveys and the TUE has always been voluntary yet strongly encouraged. On September 13, 2016, the Fukushima prefectural assembly unanimously voted to support a bill introduced to maintain the current status of TUE rather than reducing its scale. (See Bill #63 in this PDF). However, a concern has been raised by an FMU physician, Sanae Midorikawa, that an individual's desire for non-participation should be honored in view of the fact thyroid cancer screening is unlikely to reduce mortality--the purpose of most cancer screenings. Midorikawa worries more about the mental effects of cancer diagnosis. (See this post for the background information and an official translation of a newspaper article. Official translation is found here).

However, all this talk about making it easy for residents to opt out of the health surveys and the TUE is based on the assumptions that radiation effects are unlikely in Fukushima due to much smaller radiation exposure doses than Chernobyl and that the age distribution of those diagnosed with thyroid cancer--including only 1 case exposed at age 5--differs from Chernobyl where many cases were diagnosed in those who were aged 5 or younger at exposure.

Moreover, the clinical information of cancer cases is not taken into consideration. In fact, clinical data is not willingly released citing the privacy protection of the patients. Shinichi Suzuki's presentation at the 5th International Symposium came as a surprise (see this post for details). Concerning clinical features include:

  • a high rate of lymph node metastases
  • microcarcinoma (diameter ≤ 10 mm) requiring surgical intervention for various reasons--cancer cells moving outside the thyroid capsule or invading surrounding structures such as the trachea or the recurrent laryngeal nerve
  • a low female to male ratio

It is precisely these clinical features that should be discussed at the Thyroid Examination Evaluation Subcommittee, given the fact there are many unknowns about thyroid cancer in children and young adults diagnosed by screening before clinical symptoms appear.

Thyroid cancer cases outside Fukushima Prefecture
Furthermore, an independent group, "311 Fund for Children with Thyroid Cancer ," established on the principles of the Nuclear Accident Child Victims’ Support Law which was enacted but never actually carried out by the Japanese government, released some information at a December 27, 2016 press conference, shortly before the 25th Oversight Committee meeting. The 311 Fund for Children with Thyroid Cancer collects donations nationwide and offers 100,000 yen (about $864 at today's exchange rate) to an individual aged 25 or younger diagnosed with thyroid cancer and residing in 11 prefectures that received a significant amount of radioactive iodine after the Fukushima nuclear accident. The financial support is intended to help alleviate the financial strain experienced by the patients and their families in undergoing cancer treatment. This should have been covered by the Nuclear Accident Child Victims' Support Law which was intended to provide health care and financial support for relocation in areas exposed to radiation. Although the Nuclear Accident Child Victims' Support Law covers conditions which are potentially related to radiation exposure, distribution of the financial support by the 311 Fund for Children with Thyroid Cancer does not prove or certify the particular thyroid cancer case is radiation-induced. 

The 311 Fund for Children with Thyroid Cancer approved 35 of 36 application received so far (one rejected application was for a benign thyroid tumor that required surgery). Thirty-five approved cases included 26 cases from Fukushima and 9 cases outside Fukushima: 1 case each from Miyagi, Gunma, Chiba, Saitama, Nagano and Niigata, and 3 cases from Kanagawa. There were 14 males and 21 females, with the current age ranging from 10 to 25 years. In the 9 cases outside Fukushima, 87% had lymph node metastasis and 90% had total thyroidectomy. Three of 9, all from different prefectures, had lung metastases and undergoing a radioactive iodine ablation treatment, which qualifies them for an additional 100,000 yen.

Moreover, it was revealed that 2 of 26 cases from Fukushima developed symptoms after the prefecture-run TUE cleared them of and sought further medical care on their own, disqualifying them from receiving a financial support from Fukushima Prefecture.

Conclusion
It seems important to continue the TUE and even extend it outside Fukushima Prefecture, but it is also critical that the Thyroid Examination Evaluation Subcommittee be reconvened to review the data.

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Below is the summary of the basic information from each round of screening.

First Round Screening (October 2011 - April 2015)
(This is the final results as of March 31, 2016. It is unchanged from the previous report).

Total number targeted: 367,672
Number of participants in primary examination: 300,476
Number with confirmed results: 300,476
  • A1   154,607 (51.5%) (no nodules or cysts found)
  • A2   143,575 (47.8%) (nodules ≦ 5.0 mm or cysts ≦ 20.0 mm)
  • B        2,293   (0.8%) (nodules ≧ 5.1 mm or cysts ≧ 20.1 mm)
  • C               1   (0.0%) (requiring immediate secondary examination)
(Note: Cysts with solid components are treated as nodules).

Number eligible for confirmatory (secondary) examination: 2,294
Number of participants in confirmatory (secondary) examination: 2,128
Number with confirmed results : 2,086
Number of fine-needle aspiration cytology (FNAC): 545
Number suspicious or confirmed of malignancy: 116 (including one case of benign nodules)

Number with confirmed tissue diagnosis after surgery: 102
  • 1 benign nodule
  • 100 papillary thyroid cancer
  • 1 poorly differentiated cancer


Second Round Screening (April 2014 - March 2016) (see report here)

Total number targeted: 381,282
Number of participants in primary examination: 270,454
Number with confirmed results: 270,431
  • A1   108,675 (40.2%) (no nodules or cysts found)
  • A2   159,534 (59.0%) (nodules ≦ 5.0 mm or cysts ≦ 20.0 mm)
  • B        2,222   (0.8%) (nodules ≧ 5.1 mm or cysts ≧ 20.1 mm)
  • C              0   (0.0%) (requiring immediate secondary examination)
(Note: Cysts with solid components are treated as nodules).

Number of residents requiring confirmatory (secondary) examination: 2,222
Number of participants in confirmatory examination: 1,658
Number with confirmed results: 1,553
Number of FNAB: 189
Number of cases with malignancy or suspicion of malignancy: 68
Number with confirmed tissue diagnosis after surgery: 44

  • 43 papillary thyroid cancer
  • 1 "other thyroid cancer"

Third Round Screening (May 2016 - March 2018) (see report here)

Total number targeted: 336,609
Number of participants in primary examination: 49,387
Number with confirmed results: 30,253
  • A1   10,984 (36.3%) (no nodules or cysts found)
  • A2   19,058 (63.0%) (nodules ≦ 5.0 mm or cysts ≦ 20.0 mm)
  • B          211  (0.7%) (nodules ≧ 5.1 mm or cysts ≧ 20.1 mm)
  • C             0   (0.0%) (requiring immediate secondary examination)
(Note: Cysts with solid components are treated as nodules).

Number of residents requiring confirmatory (secondary) examination: 211
Number of participants in confirmatory examination: 0
Number with confirmed results: 0
Number of FNAB: 0
Number of cases with malignancy or suspicion of malignancy: 0
Number with confirmed tissue diagnosis after surgery: 0


Second Round Screening


Table 6. Cytology results (including information from Appendix 6: Number of surgeries among cases with malignancy or suspicion of malignancy) as of September 30, 2016



Sunday, October 9, 2016

Clinicopathological Findings of Fukushima Thyroid Cancer Cases: October 2016

*The Japanese version of this post can be found here.

On September 26-27, 2016, the "5th International Expert Symposium in Fukushima on Radiation and Health: Chernobyl+30, Fukushima+5: Lessons and Solutions for Fukushima’s Thyroid Question" was held in Fukushima City. The symposium was organized by the Nippon Foundation, co-organized by Fukushima Medical University, Nagasaki University, and Hiroshima University, and supported by Fukushima Prefecture, Japan Medical Association, Japan Nursing Association, and Japan Pharmaceutical Association. Program PDF can be viewed here. Information on previous symposia can be found on the following web pages: 1st symposium, 2nd symposium, 3rd symposium, and 4th symposium.

The program featured the usual suspects from the pro-nuclear camp as some of the presenters who informed the audience that "Fukushima is different from Chernobyl" and emphasized the risk of overdiagnosis from cancer screening. This post focuses on clinical information for the surgical cases presented by Shinichi Suzuki, the thyroid surgeon at Fukushima Medical University in charge of the Thyroid Ultrasound Examination.

The last time Suzuki released such information was on August 31, 2015, and it was given in a narrative form on one sheet of paper (can be found here and translated here). This time it was given as a series of PowerPoint slides with more details than ever. Screenshots of some of the slides are shown below, accompanied by narrative explanations to put the information in context. Please note that this is neither the actual transcript of his presentation nor inclusive of all the slides shown during the presentation.

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"Childhood and Adolescent Thyroid Cancer after the Fukushima NPP Accident" by Professor Shinichi Suzuki, Fukushima Medical University (PowerPoint slide PDF here)
https://www.youtube.com/watch?v=w5JwBqjgDnU
Note: Suzuki used the Thyroid Examination results released on June 6, 2016 with data as of March 31, 2016 during this presentation, although the new results as of June 30, 2016 were released on September 14, 2016.

Slide 1 



This presentation covers 125 cases of thyroid cancer that underwent surgeries at Fukushima Medical University between August 2012 and March 2016. During this time period, 132 cases underwent surgeries, 126 at Fukushima Medical University and 6 at other medical facilities. At Fukushima Medical University, 1 case was post-operatively diagnosed as a benign thyroid nodule, leaving 125 cancer cases. (Note: The August 2015 report stated 7 cases underwent surgeries at facilities other than Fukushima Medical University, but now it is 6 cases. No explanation was given regarding this discrepancy). 

As of March 31, 2016, 102 cases suspicious of cancer were operated from the first round (confirmed as 1 benign nodule and 101 cancer cases), while the second round yielded 30 cancer cases. Assuming the 6 cases operated at other medical facilities were from the first round, 125 cases presented here include 95 cases from the first round, leaving 30 cases to be accounted for by the second round.  It is not clear how many of the first round and the second round cases were actually operated at Fukushima Medical University. 125 presented here may not include 30 cases from the second round. (Note: Previous sentence was crossed out and a new sentence added on October 11, 2016). 


Slide 2


125 cases consisted of 44 males and 81 females, with the female-to-male ratio** of 1.8 to 1. 

Age at the time of the accident (i.e. age at exposure) ranged from 5 to 18 years, with an average age of 14.8 ± 2.7 years. Age at diagnosis ranged from 9 to 23, with an average age of 17.8 ± 3.1 years.

Location of tumor was ipsilateral (i.e. one-sided) in 121 cases (96.8%) and bilateral (i.e. on both sides) in 4 cases. In 121 ipsilateral cases, 67 were located in the right lobe, 53 in the left lobe, and 1 in the isthmus which connects together the lower thirds of the right and left lobes.

**Thyroid cancer is known to occur more commonly in females. The female to male ratio tends to increase with age. For instance, the female to male ratio in the 2009 US study is 4.3:1 with 94.5% of cases ≥ age 10 [1. In the 1995 study of the cancer registry data from 1963 to 1992 in England and Wales, the female to male ratio was 1.25:1 in ages 5-9 and 3.1:1 in ages 10-14 [2]. The female to male ratio is also known to decrease in the radiation exposed cases. In the 2008 study that compared thyroid cancer cases (exposed to radiation) in Belarus, Ukraine and Russia after the Chernobyl accident with unexposed cases in the same region as well as in UK and Japan, the female to male ratio was 4.2:1 overall, 2.4:1 in age <10, 5.2:1 in age ≥10 in the unexposed cases, whereas the female to male ratio was 1.5:1 overall, 1.3:1 in age <10, and 1.6:1 in age ≥10 in the exposed cases [3].

Slide 3


TNM classification is explained below. Japan has its own clinical guidelines on cancers, but the TNM classification is essentially the same with the exception of the "Ex" notation which refers to the degree of extension outside the thyroid capsule: 
Ex1 means minimal extension (example: extension to sternothyroid muscle or perithyroid soft tissues) and is equivalent to T3.
Ex2 means further extension and is equivalent to T4.

Prefix "c" refers to "clinical" while "p" refers to "pathological."

Pre-operative tumor size here refers to the largest diameter measured by ultrasound. It ranged from 5 mm to 53 mm with average of 14.0 ± 8.5 mm. (Note: The largest pre-op diameter was 45.0 mm for the first round and 35.6 mm for the second round. It is unclear where "53 mm" came from).

44 had tumor size ≤ 10 mm and limited to the thyroid.
57 had tumor size > 10 mm but ≤ 20 mm and limited to the thyroid. 
12 had tumor size > 20 mm but ≤ 40 mm and limited to the thyroid.
12 had tumor size > 40 mm and limited to the thyroid, or any size tumor minimally extending outside the thyroid.

28 had metastases to the regional lymph node. 
5 had lymph node metastases near the thyroid, within the central compartment of the neck.
23 had lymph node metastases to further areas of the neck.

3 had distant metastases to the lungs. This is the first time that any clinical details of the distant metastasis cases are given.
1) Male. Age at exposure 16, age at surgery 19. 
Pre-operative: cT3 cN1a cM1. Tumor size > 40 mm and limited to thyroid or any size with minimal extension outside the thyroid. Metastasis to lymph nodes in the central compartment of the neck. Distant metastasis.
Post-operative: pT3 pEx1 pN1a pM1. Tumor size > 40 mm and limited to thyroid or any size with minimal extension outside the thyroid. Minimal extension outside the thyroid. Metastasis to lymph nodes within the central compartment of the neck. Distant metastasis.
2) Male. Age at exposure 16, age at surgery 18.
Pre-operative: cT3 cN1b cM1. Tumor size > 40 mm and limited to thyroid or any size with minimal extension outside the thyroid. Metastasis to the neck lymph nodes outside the central compartment. Distant metastasis.
Post-operative: pT2 pEx0 pN1b pM1. Tumor size > 20 mm but ≤ 40 mm and limited to the thyroid. No extension outside the thyroid. Metastasis to the neck lymph nodes outside the central compartment. Distant metastasis.
3) Female. Age at exposure 10, age at surgery 13.
Pre-operative: cT1b cN1b cM1. Tumor size > 1 cm but ≤ 2 cm, limited to the thyroid. Metastasis to the neck lymph nodes outside the central compartment. Distant metastasis.
Post-operative: pT3 pEx1 pN1b pM1. Tumor size > 40 mm and limited to thyroid or any size with minimal extension outside the thyroid. Minimal extension. Metastasis to the neck lymph nodes outside the central compartment. Distant metastasis.


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TNM classification for differentiated thyroid cancer from the American Cancer Society website.
Primary tumor (T)
T indicates the size of the primary tumor and whether it has grown into the nearby area.
T1a: Tumor ≤ 1 cm, limited to the thyroid
T1b: Tumor > 1 cm but ≤ 2 cm in greatest dimension, limited to the thyroid
T2: Tumor size > 2 cm but ≤ 4 cm, limited to the thyroid
T3: Tumor size >4 cm, limited to the thyroid or any tumor with minimal extrathyroidal extension (eg, extension to sternothyroid muscle or perithyroid soft tissues)
T4a: The tumor is any size and has grown extensively beyond the thyroid gland into nearby tissues of the neck, such as the larynx (voice box), trachea (windpipe), esophagus (tube connecting the throat to the stomach), or the nerve to the larynx. This is also called moderately advanced disease.
T4b: The tumor is any size and has grown either back toward the spine or into nearby large blood vessels. This is also called very advanced disease.
Regional lymph nodes (N)
Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes:
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
     N1a: Metastases to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)
     N1b: Metastases to unilateral, bilateral, or contralateral cervical (levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal lymph nodes (level VII) 
Distant metastasis (M)
M0: No distant metastasis is found
M1: Distant metastasis is present
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Slide 4


This slide is similar to Slide 3, except it describes why surgeries were conducted in 44 "cT1a cN0 cM0" cases with tumor ≤ 10 mm without any pre-operative clinical evidence of lymph node or distant metastases. (Surgery for thyroid "microcarcinoma," i.e. cancer ≤ 10 mm, is controversial in adults).

11 of 44 cases underwent surgeries despite the recommendation of non-surgical, observational follow-ups. Remaining 33 cases had suspicion for one or more of the following conditions:
20 cases: Ex1 or Ex2 (extension beyond the thyroid capsule)
3 cases: N1a (metastases to lymph nodes within the central compartment of the neck)
10 cases: Invasion of the recurrent laryngeal nerve
7 cases: invasion of the trachea
1 case: Graves disease
1 case: Ground-glass opacity (GGO) of the lungs

Slide 5


11 underwent total thyroidectomy where both right and left lobes of the thyroid were removed. Skin incision was limited to 4-5 cm.
114 had hemi-thyroidectomy where one lobe of the thyroid was removed. Skin incision was limited to 3cm.

All cases underwent the central lymph node dissection. 24 cases also had dissection of the lateral neck lymph nodes. 

Japan's clinical guidelines use a slightly different classification system of the regional lymph node levels (described at the end). Furthermore, "D classification" or "D number" is used to describe the extent of the lymph node dissection, which apparently corresponds to the selective neck dissection (SND) defined by the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery [4]. The equivalent SND notation is shown when possible for easier understanding.

D0: No dissection, or the degree of dissection not reaching D1.
D1: Dissection of the central compartment lymph nodes (prelaryngeal, pretracheal, paratracheal and prethyroidal). Can be unilateral of bilateral. Equivalent to SND (VI).
D2a: D1 plus dissection of middle jugular and lower jugular nodes. Equivalent to SND (III, IV, VI).
D2b: D2a plus dissection of upper jugular and posterior triangle nodes. Equivalent to SND (II-V, VI).
D3a: Bilateral D2a. Equivalent to bilateral SND (III, IV, VI)
D3b: Bilateral D2b, or D2a plus contralateral D2b.
D3c: D2 or D3 plus dissection of superior mediastinal nodes.

Slide 6
This slide shows what was found during the surgery and subsequent pathological examination of the excised tissues and lymph nodes. 



Shown here side by side with the pre-operative findings, it becomes clear that fewer cases are limited to thyroid and ≤ 20 mm, while  more cases turned out to have minimal extension and the regional lymph node involvement.

Notable is the number and percentage of cases confirmed to have minimal extension outside the thyroid capsule, pEx1. This number, 49 (40%), is the same as pT3, suggesting pT3 in this group denotes any size tumor with minimal extension outside the thyroid capsule. 

Even more notable is the number of regional lymph node metastases. 5 cases of cN1a turned out to be 76 cases of pN1a. Overall, 97 (77.6%) of 125 had regional lymph node metastasis.





Slide 7


This slide shows the post-operative findings of 44 "cT1a cN0 cM0" cases with tumor smaller than 10 mm without any pre-operative clinical evidence of lymph node or distant metastases described in Slide 4.

Of 11 cases that underwent surgery against the recommendation of non-surgical, observational follow-ups, 2 cases turned out to be pT1a pN0 pEx0, meaning the tumor was ≤ 10 mm without any regional lymph node involvement or extension beyond the thyroid capsule. 

Of remaining 33 cases that had indications for surgery as described in Slide 4, 3 cases turned out to be pT1a pN0 pEx0.

Overall, 5 of 44 cases with tumor size ≤ 10 mm turned out to have no lymph node involvement or extension beyond the thyroid capsule, suggesting these 5 cases might not have actually needed surgery at the time. But this is in hindsight, and it should be remembered 33 cases originally did have clear surgical indications. (Curiously, the previous report from August 2015 states this number was "8." No explanation was given by Suzuki as to the discrepancy. However, his admittance of "a few percent of recurrence" might allow for speculation that 3 of 8 cases recurred and no longer was classified "pT1a pNO pEx0." It should be noted this has not been confirmed by Suzuki. It is expected he might discuss clinical details such as the recurrence rate during his presentation on the Thyroid Examination at the Annual Meeting of the Japan Thyroid Association on November 13-15, 2016, in Tokyo. 

Slide 8


This slide shows the types of thyroid cancer found in 125 cases. 121 had papillary thyroid cancer (PTC), 3 had poorly differentiated thyroid cancer, and 1 had "other" thyroid cancer. 

It should be noted that 2 of 3 cases of poorly differentiated thyroid cancer has since been reclassified as papillary thyroid cancer with unspecified subtypes in accordance with the revision of the thyroid cancer clinical guidelines (see this post for more information). 

Regarding one case of "other" thyroid cancer, it was previously explained by Akira Ohtsuru, head of the Thyroid Examination, that the patient had differentiated thyroid cancer that is not considered to be related to radiation and categorized as "other" according to the classification in the seventh revision of Japan's unique thyroid cancer diagnostic guidelines released in November 2015. 

121 cases of papillary thyroid cancer showed 4 subtypes/variants:
110 cases of classical type
4 cases of follicular variant*
3 cases of diffuse sclerosing variant
4 cases of cribriform-morular variant**

A special notation was made by Suzuki that no solid variant of PTC--the most common subtype in Chernobyl--was seen. This is one of the claims repeated by the officials to emphasize the Fukushima cancer cases are unlike those in Chernobyl, i.e. unlikely to be due to the radiation effects. However, solid variant PTC is not exclusive to radiation-induced thyroid cancer, and a high frequency of solid variant PTC observed in Chernobyl might be due to the young age of the early cases [5,6,7]. Moreover, in one study, solid variant was not seen in Japanese childhood PTC [8]. 

*Recently, encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) was reclassified as “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP) [9]. However, cases of the follicular variant of papillary thyroid cancer found here are not assumed to be EFVPTC since they were never reclassified as non-cancer. This subject never came up during the Oversight Committee meetings.
**Cribriform-morular variant is usually associated with familial adenomatosis polyposis.

Slide 9
This slide shows algorithms for diagnosis and treatment of papillary thyroid cancer according to the Japanese clinical guidelines.


Slide 10
This slide shows a comparison of surgical methods between Belarus and Fukushima. Most cases in Fukushima underwent hemithyroidectomy or lobectomy, whereas total thyroidectomy was the most common surgical method in Belarus.


Suzuki mentioned that extra care has been taken to reduce complications from surgeries, and hemithyroidectomy was employed when possible to decrease the lifetime need for thyroid hormone supplementation. Also, this article by Japan's top thyroid surgeons states, "At present, Western countries adopted almost routine total thyroidectomy with radioactive iodine (RAI) ablation, while limited thyroidectomy with extensive prophylactic lymph node dissection has traditionally been performed for most patients in Japan.(...) In Japan, however, limited thyroidectomy such as subtotal thyroidectomy and lobectomy with isthmectomy has been traditionally adopted as the standard. This is partially because the capacity to perform RAI therapy is limited due to legal restrictions, and RAI therapy is not considered cost effective by the healthcare system in Japan. [10]"

Slide 11
This slide shows the genetic mutation profile in different study groups. 63.2% of 52 cases from Fukushima was shown to have BRAF mutation. In the 2015 study by Mitsutake et al.[11] shown in the green box, 43 (63.2%) of 68 cases are shown to be positive for BRAF V600E point mutation. The same study also shows 10.3% was positive for RET/PTC rearrangements (6 cases of RET/PTC1 and 1 case of RET/PTC3) and 4 cases (5.9%) had ETV6/NTRK3 rearrangement. (It's unclear where "n=52" and 8.8% of TRK fusion came from for the Fukushima column, as the Mitsutake study has n=68 and did not test for TRK fusion. It's also unclear where the Japanese adult data came from. Literature search revealed the BRAF frequency in PTC of Japanese adults varied in a wide range: 28.8% [12], 38.2% [13], 38.4% [14] , 53% [15], and 82.1% [16]). 

The official stance is that the genetic alterations observed in Fukushima cases are similar to what is seen in typical adult papillary thyroid cancer and "probably reflects genetic status of all sporadic and latent thyroid carcinomas in the young Japanese population [11]." In other words, the official assert that the genetic profile appears consistent with the official claim that screening is diagnosing spontaneous and latent cancers which might not have been detected without screening.

However, literature varies in regards to how the genetic mutations are associated with radiation exposure, age, and iodine status. RET/PTC rearrangements, frequently seen in Chernobyl, are associated with both radiation-induced and spontaneous thyroid cancer [17], more common at younger age and in iodine deficient areas [18]. BRAF mutation is known to be seen more frequently in older age, but recent studies showed BRAF V600E was present in 36.8% (median age 13.7 years) [19] and 63% (median age 18.6 years) [20] of pediatric papillary thyroid carcinoma. BRAF mutation were associated with high iodine intake in China [21], while no difference in BRAF V600E frequency was found between iodine-rich and iodine-deficient countries recently [16].



Slide 12


This slide shows a graph with age distribution of thyroid cancer patients in Ukraine and Fukushima in different post-accident time periods, compiled by superimposing 2 graphs from Letter to the Editor of Thyroid [21]. Blue bars are for 1986-1990 in Ukraine (first 4 years after the Chernobyl accident) and red bars are for 2011-2013 in Fukushima (first 3 years after the Fukushima accident), both time periods representing "latency" for radiation-induced thyroid cancer in children. Orange bars are for 1990-1993 in Ukraine--after the latency period--showing a large increase in thyroid cancer cases in Ukrainian residents who were 18 or younger when the accident happened. Increased number of cases in those who were age 5 or younger set this time period apart. The year 1990 is also when large-scale screening programs began, initiated by international organizations [22]. 

The age distribution is "strikingly similar" between the first 4 post-accident years in Ukraine (blue bars) and the first 3 years in Fukushima (red bars), as acknowledged by the letter. However, the letter is inconsistent in claiming "if thyroid cancers in Fukushima were due to radiation, more cases in exposed preschool-age children would have been expected" and defining the first 4 years as "latency." This illogical claim is also seen in a slightly different format as a comparison between different post-accident periods [23].

Concluding summary
The official stance is that thyroid cancer cases detected after the Fukushima accident are more likely due to the screening effect, meaning the screening discovered spontaneous and latent cancers that were not causing any symptoms and would not become clinically significant until much later if it weren't for the screening. However, clinical details show that most cases were not so innocuous: extending outside thyroid gland; metastasizing to cervical lymph nodes or even to the lungs; or invading vital structures such as the trachea and the recurrent laryngeal nerve. A few cases may represent overdiagnosis/overtreatment, but for the vast majority of the cases, surgeries were clearly indicated medically. It's even questionable if some of the cases were truly asymptomatic. Detailed, specific questions regarding potential symptoms were not asked, at least in the information sheet submitted with the consent form. Whether further questioning about the symptoms occurred during the confirmatory examination is unknown. More transparency is warranted.

Female to male ratio seems higher than expected considering the average age of the patients. Histological type and genetic alterations commonly seen in Chernobyl may not be observed in Fukushima cases, but this could be due to variations in age, iodine status, or ethnic background between the two groups. 

The phrase, "Fukushima is not Chernobyl" was frequently repeated during the symposium. Indeed, it is time that Fukushima data--disclosed with transparency--be given a fresh look by unbiased experts who can analyze it as is, rather than endless comparisons with Chernobyl to prematurely deny radiation effects. 


*****
Classification of cervical lymph nodes by the Japanese clinical guidelines

I: Prelaryngeal nodes: LN anterior to the thyroid cartilage and the cricoid cartilage
II: Pretracheal nodes: LN anterior to trachea, dissectible posteriorly from the inferior border of thyroid 
III: Paratracheal nodes: LN lateral to trachea, extending inferiorly to where it is dissectible from the neck and superiorly where recurrent laryngeal nerve enters trachea.
IV: Prethyroid nodes: LN adjacent to anterior and lateral parts of thyroid. Laterally includes LN attached to thyroid when middle thyroid artery is ligated and cut. (Equivalent to the AJCC Level IV: lower jugular nodes)
   (I, II, III and IV are equivalent to the AJCC Level VI: anterior compartment LN)
V: Superior internal jugular nodes: LN along internal jugular vein but superior to the inferior border of cricoid cartilage. This is further subdivided into superior and inferior at the bifurcation of common carotid artery
   Va LN: inferior to the bifurcation of common carotid artery (equivalent to the AJCC Level II: upper jugular nodes)
   Vb LN: superior to the bifurcation of common carotid artery (equivalent to the AJCC Level III: middle jugular nodes)
VI: Inferior internal jugular nodes: LN along internal jugular vein, inferior to the inferior border of cricoid cartilage. Includes LN in supraclavicular fossa. 
VII: Posterior triangle nodes: LN located in posterior triangle bordered by anterior border of sternocleidomastoid muscle, posterior border of trapezius muscle, and omohyoid muscle.
VIII: Submandibular nodes: LN in the submandibular triangle.
IX: Submittal nodes: LN in the submental triangle.
   (VIII and IX are equivalent to the AJCC Level I)
X: Superficial cervical  nodes: LN superficial to superficial layer of the deep cervical fascia enclosing sternohyoid and sternocleidomastoid muscles.
XI: Superior mediastinal nodes: LN unresectable by neck dissection
   (Equivalent to the AJCC Level VII: superior mediastinal nodes)

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