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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 (starts around 1:45:25 in the video embedded below, with Japanese interpretation).




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. 


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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)

References
[1] Hogan AR, Zhuge Y, Perez EA, Koniaris LG, Lew JI, Sola JE. Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. J Surg Res. 2009 Sep;156(1):167-72. doi: 10.1016/j.jss.2009.03.098.
[2] Harach HR, Williams ED. Childhood thyroid cancer in England and Wales. British Journal of Cancer. 1995;72(3):777-783.
[3] Williams ED, Abrosimov A, Bogdanova T, et al. Morphologic Characteristics of Chernobyl-Related Childhood Papillary Thyroid Carcinomas Are Independent of Radiation Exposure but Vary with Iodine Intake. Thyroid. 2008;18(8):847-852. doi:10.1089/thy.2008.0039.
[4] Robbins K, Clayman G, Levine PA, et al. Neck Dissection Classification Update: Revisions Proposed by the American Head and Neck Society and the American Academy of Otolaryngology–Head and Neck Surgery. Arch Otolaryngol Head Neck Surg. 2002;128(7):751-758. doi:10.1001/archotol.128.7.751.
[5] Ory C, Ugolin N, Schlumberger M, Hofman P, Chevillard S. Discriminating Gene Expression Signature of Radiation-Induced Thyroid Tumors after Either External Exposure or Internal Contamination. Genes. 2012;3(1):19-34. doi:10.3390/genes3010019.
[6] Tronko MD, Bogdanova TI, Komissarenko IV, Epstein OV, Oliynyk V, Kovalenko A, Likhtarev IA, Kairo I, Peters SB, and LiVolsi VA. Thyroid carcinoma in children and adolescents in Ukraine after the Chernobyl nuclear accident. Cancer. 1999;86:149–156. doi:10.1002/(SICI)1097-0142(19990701)86:1<149::AID-CNCR21>3.0.CO;2-A.
[7] LiVolsi, VA, et al. The Chernobyl Thyroid Cancer Experience: Pathology. Clinical Oncology. 23(4):261-267.
[8] Williams ED, Abrosimov A, Bogdanova T, et al. Morphologic Characteristics of Chernobyl-Related Childhood Papillary Thyroid Carcinomas Are Independent of Radiation Exposure but Vary with Iodine Intake. Thyroid. 2008;18(8):847-852. doi:10.1089/thy.2008.0039.
[9] Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. JAMA Oncol. 2016;2(8):1023-1029. doi:10.1001/jamaoncol.2016.0386.
[10] Ito Y. and Miyauchi A. Thyroidectomy and Lymph Node Dissection in Papillary Thyroid Carcinoma. Journal of Thyroid Research. 2011; Article ID 634170, 6 pages. doi:10.4061/2011/634170.
[11] Mitsutake N, Fukushima T, Matsuse M, et al. BRAFV600E mutation is highly prevalent in thyroid carcinomas in the young population in Fukushima: a different oncogenic profile from Chernobyl. Scientific Reports. 2015;5:16976. doi:10.1038/srep16976.
[12] Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T, and Yamashita S. Clinical Implication of Hot Spot BRAF Mutation, V599E, in Papillary Thyroid Cancers. The Journal of Clinical Endocrinology & Metabolism. 2003;88(9):4393-4397. 
[13] Nasirden A, Saito T, Fukumura Y, et al. Virchows Arch (2016). doi:10.1007/s00428-016-2027-5.
[14] Ito Y, Yoshida H, Maruo R, et al. BRAF Mutation in Papillary Thyroid Carcinoma in a Japanese Population: Its Lack of Correlation with High-Risk Clinicopathological Features and Disease-Free Survival of Patients. Endocrine Journal. 2009;5(1):89-97. 
[15] Fukushima T, Suzuki S, Mashiko M, et al. BRAF mutations in papillary carcinomas of the thyroid. Oncogene. 2003;22:6455–6457. doi:10.1038/sj.onc.1206739.
[16] Vuong HG, Kondo T, Oishi N, et al. Genetic alterations of differentiated thyroid carcinoma in iodine‐rich and iodine‐deficient countries. Cancer Medicine. 2016;5(8):1883-1889. doi:10.1002/cam4.781.
[17] Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, and Fagin JA. Distinct Pattern of ret Oncogene Rearrangements in Morphological Variants of Radiation-induced and Sporadic Thyroid Papillary Carcinomas in Children. Cancer Res. May 1997;57(9):1690-1694.
[18] Leeman-Neill RJ, Brenner AV, Little MP, Bogdanova TI, Hatch M, Zurnadzy LY, Mabuchi K, Tronko MD, and Nikiforov YE. RET/PTC and PAX8/PPARĪ³ chromosomal rearrangements in post-Chernobyl thyroid cancer and their association with iodine-131 radiation dose and other characteristics. Cancer. 2013;119:1792–1799. doi:10.1002/cncr.27893.
[19] Givens DJ, Buchmann LO, Agarwal AM, Grimmer JF, and Hunt JP. BRAF V600E does not predict aggressive features of pediatric papillary thyroid carcinoma. The Laryngoscope. 2014;124:E389–E393. doi: 10.1002/lary.24668.
[20] Henke LE, Perkins SM, Pfeifer JD, Ma C, Chen Y, DeWees T, and Grigsby PW. BRAF V600E mutational status in pediatric thyroid cancer. Pediatr Blood Cancer. 2014;61:1168–1172. doi:10.1002/pbc.24935.
[21] Guan H, Ji M, Bao R, et al. Association of High Iodine Intake with the T1799A BRAF Mutation in Papillary Thyroid Cancer. The Journal of Clinical Endocrinology & Metabolism. 2009;94(5):1612-1617. doi:10.1210/jc.2008-2390.
[22] International Advisory Committee. The International Chernobyl Project. Assessment of radiological consequences and evaluation of protective measures. 
Technical Report. Vienna: International Atomic Energy Agency; 1991.
[23] Takamura N, Orita M, Saenko V, Yamashita S, Nagataki S, and Demidchik Y. Radiation and risk of thyroid cancer: Fukushima and Chernobyl. The Lancet Diabetes & Endocrinology. 2016;4(8):647. doi:10.1016/S2213-8587(16)30112-7.

Friday, September 30, 2016

Translation of a News Article: "Thyroid Cancer--A Few Percent Recurred After Surgeries"

On September 27, 2016, an article titled "Thyroid Cancer: A Few % Recurred After Surgeries" appeared on the website of NHK Fukushima Station. The URL shows an error message because the article is no longer shown online due to a short posting time on local station websites: newer articles push older ones off the slot, and this article, posted at 1:05 pm likely was pushed off the website as the evening news articles rolled in. NHK does not maintain archives of its articles on their website. Luckily, the article was archived here. English translation is provided below, and more detailed information on the surgical cases is available in this post.

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Thyroid Cancer: A Few Percent Recurred After Surgeries

A physician who has been conducting surgeries on children diagnosed with thyroid cancer revealed for the first time that there has been a few percent of the cases recurred after surgery. These cancer cases were diagnosed during the Thyroid Examination conducted by Fukushima Prefecture after the nuclear accident.

Professor Shinichi Suzuki from Fukushima Medical University revealed the fact during the international symposium about thyroid cancer that began on September 26th in Fukushima City.

Fukushima Prefecture has been conducting the thyroid examination to assess the condition of the thyroid gland in about 380,000 residents who were age 18 or younger at the time of the accident. During the symposium, Professor Suzuki presented information such as  detailed conditions and surgical methods on 125 cases—diagnosed by the prefectural thyroid examination—which underwent surgeries at Fukushima Medical University Hospital between August 2012 and March 2016.

The presentation stated 28 (22.4%) of 125 had lymph node metastasis around the neck and 3 (2.4%) had distant metastasis to lungs.

Histopathological classification showed 121 with a common type of thyroid cancer called “papillary thyroid cancer.” The “solid variant” that increased after the Chernobyl nuclear accident was not seen.

Regarding the operation method, the entire thyroid gland (consisting of right and left lobes) was removed in 11, while only one lobe was taken out in the remaining 114.
While declining to give the exact number, Professor Suzuki revealed for the first time that a few percent of the operated patients had recurrence.

The symposium is expected to put together recommendations to Fukushima Prefecture in the afternoon of the 27th regarding how to deal with the thyroid cancer issues in the future.

13:05 (1:05pm), September 27, 2016
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(Note: Literal translation of the original Japanese text refers to the recurrence being "several" percent, but what Suzuki actually said at the symposium was "a few" percent).

Thursday, September 15, 2016

Fukushima Thyroid Examination September 2016: 135 Thyroid Cancer Cases Confirmed (101 in the First Round and 34 in the Second Round)

135 Thyroid cancer cases confirmed in Fukushima as of June 30, 2016--101 in the first round and 34 in the second round (Total of 174 cases including suspected cancer cases--115 in the first round and 59 in the second round).


The 24th Prefectural Oversight Committee for Fukushima Health Management Survey convened in Fukushima City, Fukushima Prefecture, on Wednesday, September 14, 2016. 

Among other information, the Oversight Committee released the latest results (as of June 30, 2016) of the second round screening, which was conducted over a two-year period from April 2014 to March 2016. The second round screening is still ongoing in terms of the confirmatory examination, so the results are not complete.

An official English translation of the results is available here. The narrative below contains some information gathered from the live webcast of the Oversight Committee meeting and the subsequent press conference. 

Overview

As of June 30, 2016, there are 2 more cases with malignancy or suspicion of malignancy from the second round, for a total of 174 (175 including the single case of post-surgically confirmed benign nodule). The number of surgically confirmed cancer cases, excluding the aforementioned case of benign nodule, now totals 135 (101 from the first round and 34 from the second round), and the remaining 39 (14 from the first round and 25 from the second round) await surgical confirmation. 

Although the final results of the second round screening were widely anticipated at this Oversight Committee meeting, it turned out only two-thirds of those who were eligible for the confirmatory examination actually participated as of June 30, 2016. (Many of them might have undergone the confirmatory examination during the summer break, typically from late July through August).

Since the last results were released, only 4 additional cases from the second round have been operated on. Post-surgical pathological examination of the resected thyroid gland tissue confirmed 3 as papillary thyroid cancer and 1 as "other thyroid cancer" according to the classification in the seventh revision of Japan's unique thyroid cancer diagnostic guidelines released in November 2015.


Full-Scale Screening
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 in April 2014, including those who were born in the first year after the accident. There are 381,281 eligible individuals born between April 2, 1992 and April 1, 2012. As of June 30, 2016, 270,378 actually participated in the primary examination at the participation rate of 70.9% (lower than 81.7% at the first round screening). 270,327 have received confirmed results of the primary examination, and 2,217 (increased by 156 since the last Oversight Committee meeting) turned out to be eligible for the confirmatory examination. 

The confirmatory examination is still only about two-thirds complete. Of 1,476 who actually underwent the confirmatory examination, 1,379 received confirmed results including 176 that underwent fine-needle aspiration cytology (FNAC). FNAC revealed 59 cases suspicious for cancer. Confirmation of thyroid cancer requires pathological examination of the resected thyroid tissue obtained during surgery. As of June 30, 2016, 34 underwent surgery and 33 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 a differentiated thyroid cancer that is not known to be related to radiation exposure.

Newly diagnosed cases in the second round
In the second round, 2 cases were newly diagnosed by FNAC to be malignant or suspicious of malignancy. They were 2 females (age at exposure: 12 and 14). Their places of residence at exposure were Iwaki City and Tadami Town, both of which are FY 2015 target municipalities.

In relation to the still ongoing confirmatory examination, special attention should be paid to the participation rate in Iwaki City. Of 45,228 Iwaki City residents who participated in the second round screening, 376 were eligible for the confirmatory examination. Only 172 have actually participated in the confirmatory examination as of June 30, 2016, and 134 of them have confirmed results. Thus, more confirmatory examination results are expected from Iwaki City, the largest of the FY2015 target municipalities. 

Prior diagnostic status of the cases newly diagnosed in the second round
Of 59 total cases with malignancy or suspicion of malignancy in the second round, 28 were A1, 26 were A2, and 5 were B in the first round.  

28 cases that were A1 in the first round screened suspicious for malignancy in the second round. This would appear to be a new onset after the first round since A1 cases by definition have no ultrasound findings of cysts or nodules.

In 26 cases that were A2 in the first round, 7 were nodules and 19 were cysts. (Two cases with malignancy or suspicion of malignancy reported this time are deduced to be A2 cysts in the first round). Thus the majority of the second round cases appeared to have developed thyroid cancer in 2 to 3 years since the first round. However, Ohtsuru explained this time that at certain ages in children, existing ultrasound lesions may not be visible until a few years later, suggesting there might have been invisible lesions in the first round which only became visible as the child aged.


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: 381,281
Number of participants in primary examination: 270,378
Number with confirmed results: 270,327
  • A1   108,619 (40.2%) (no nodules or cysts found)
  • A2   159,491 (59.0%) (nodules ≦ 5.0 mm or cysts ≦ 20.0 mm)
  • B        2,217   (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 eligible for confirmatory (secondary) examination: 2,217
Number of participants in confirmatory examination: 1,476
Number with confirmed results: 1,379
Number of FNAB: 176
Number of cases with malignancy or suspicion of malignancy: 59
Number with confirmed tissue diagnosis after surgery: 34

  • 33 papillary thyroid cancer
  • 1 "other thyroid cancer"

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

Total number targeted: 381,172
Number of participants in primary examination: 17,481
Number with confirmed results: 0




Unofficial translation of selected tables

Second Round Screening


Table 1. Primary examination coverage as of June 30, 2016

Table 2. Number and proportion of children with nodules/cysts as of June 30, 2016

Table 3. Participation rates by age group as of June 30, 2016

Table 4. Comparison with the Initial (Preliminary Baseline) Screening as of June 30, 2016

Note 1: Top line refers to the results of the Preliminary Baseline Screening for confirmed results of the Full-Scale Screening.

            It is not the breakdown of the total Preliminary Baseline Screening results, 300,476.

Note 2: Top line refers to the breakdown of the Full-Scale Screening results in a given category of the Preliminary Baseline Screening results. 
            Bottom line shows the proportion in %.

Table 5. Confirmatory testing coverage and results as of June 30, 2016

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

Figure 3. Distribution of cases with malignancy or suspicion of malignancy by age (as of March 11, 2011) and sex (females in white and males in gray)


Figure 5.  Estimated external effective doses of those who submitted basic survey questionnaire as of June 30, 2016 (females in white and males in blue) 


Third Round Screening

Table 1. Primary examination coverage as of June 30, 2016