Clinicopathological Findings of Fukushima Thyroid Cancer Cases: October 2016

*The Japanese version of this post can be found here.
**Notations were inserted in italics on September 30, 2018 for Slides 1 and 2.

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 (FMU) in charge of the clinical part 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=Gsq1_eF93V8

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.)
(Note on September 30, 2018: This discrepancy was clarified at the 32nd Oversight Committee held on September 5, 2018. It turns out 132 cases included one surgery conducted in April 2016, and it was confirmed that 124 surgeries were conducted at FMU and 7 at other medical facilities as of March 31, 2016. Below is the corrected slide in Japanese that reflects changes in numbers. For Slide 2 that shows characteristics on 125 FMU surgical cases, the single April 2016 case was added back to 124. For details, see this post.)

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

(Note on September 30, 2018: 125 thyroid cancer cases shown in Slide 2 include 1 surgical case from April 2016. For details, see this post.) 

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 ***** 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, officials 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. BRAF^V600E 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/PPARγ 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.