細胞病理のエキスパートを目指す人へ

Dear Dr Kakudo
I wanted to write to you about how I feel on your second opinion diagnosis. For people who will read this story for the first time I would like to simply explain my situation. I’m a male at my 37. I had lobectomy operation due to a thyroid nodule of 2.7cm in size at my left thyroid lobe. Pathology report after surgery said “Follicular Variant of Papillary Carcinoma” and I was advised to go for completion surgery and radioactive iodine (RI) treatment.
After reading many articles including yours about borderline lesions I started to question if surgery was the best option for my health or not. Then I started to follow “thyroid cancer survivors association group” at “inspire.com”. Following this site gave me a better understanding of how people feel without thyroid gland, short and long term side effects. And based on an advice from a friend from that group I decided to contact you and you kindly accepted to give me your second opinion.
Your diagnosis result says “findings are incomplete and do not fulfill histopathologic criteria for either follicular carcinoma or papillary carcinoma”. And this type of tumor are “practically benign after simple excision”. This difference in opinion obviously makes a big change for management of the disease. No need for completion surgery and no need for RI treatment.
As a patient going through all this on one hand I feel lucky because it’s not a genuine cancer case where none of above mentioned discussion could be possible. I also feel lucky because I had a chance to read and better understand risks and downsides of surgery and RI treatment before deciding anything further. On the other hand not going down that road may have other risks in specific cases and today we are not 100% sure about long term outcome for each individual. However statistically there is a strong evidence that we are almost 100% sure (your study shows 0,03% missing malignancy judging) there will be no recurrence or distant metastasis.
Reflecting on my case and many others it’s clear to me that there is a difference in opinion between pathologists and this has a direct impact on management of the disease. Important point to me is to give enough information to patients so that they can make their own decisions. Not just say this is your problem and this is the one and only solution. Take it or not! I could have felt much better if risks of surgery and RI and not doing that was explained to me objectively. At the end it’s my life and I have to make a decision. Why should I have to find out difficulties in diagnosis and even classification of borderline lesions by myself? How many people will (be able to) do what I did? And how many people will just do what is told? Therefore how many people will possibly be treated for nothing? And their quality of life and feeling about their health is impacted adversely for the rest of their lives.
I hope answers to above questions will be discussed more and more in the coming years. And until we find a clear method to identify what is definitely malignant and what is not I hope doctors around the world will give more information to their patients and explain real difficulty to make this identification. And let people decide what is best for themselves.
Finally I want to say thank you for your second opinion diagnosis which made a big change in my life. And a big thank you for your life time studies and sharing what you believe is right to make a change in people’s lives.

甲状腺学会編集、甲状腺結節取扱い診療ガイドラインが南江堂から出版されました。甲状腺穿刺細胞診と病理診断の問題点について我々病理医4名で取り組みました。ここでの新規軸は、甲状腺穿刺細胞診の診断様式に、伊藤病院、隈病院など日本の甲状腺専門医療機関で開発された診断様式を取り上げたことです。一般病理医、細胞検査士に同レベルでの診断がどこまで可能かと疑問が投げかけられましたが、わたくしは可能と強くはねつけました。是非病理専門医、細胞診専門医、細胞検査士の方々は、ご一読いただいて、甲状腺専門医療機関の独自に開発した診断様式の趣旨をくみ取っていただきたいと思います。細かいことは省略いたしますが、現在欧米で普及しています、べセスダ診断様式、英国様式と診断用語や、臨床的対応に違いがありますが、細胞所見には全く違いがありません。どの診断用語を用いるか、臨床側パートナーとご相談の上お決めください。このHPにご意見を頂ければ幸いです。具体的には、嚢胞液が得られた検体で、濾胞上皮細胞が6集塊得られないとき、べセスダでは全例再検査、検体不適の診断となります。甲状腺学会のガイドラインでは、嚢胞液が確認されれば、良性と診断し、画像で悪性も考えられる例のみを再検査とします。画像診断が進んでいる日本の実際的な方針です。

2013年前半の論文活動を報告いたします。 論文としては

1. Morioka T, Ohba K, Morita H, Takahashi G, Uchida H, Matsushita A, Sasaki S, Oki Y, Suda T, Kakudo K, Yoshino A: Non-islet cell tumor-induced hypoglycemia associated with macronodular pulmonary metastases from poorly differentiated thyroid carcinoma. Thyroid, 2013 May 23 Epub ahead of print.
2. Kakudo K, Mori I, Liu Z, Hui Z, Kakudo M, Wakasa T: Papillary microcarcinoma and microtumor of the thyroid gland. J Basic & Clin Med, 2:1-6, 2013.
3. Wakasa T, Shintaku M, Tanaka S, Yamada K, Li Y, Kakudo K: Morphological Changes of follicular cells in Hashimoto’s disease: A possible cause of overdiagnosis in cytology. J Basic & Clin Med, 2:12-16, 2013.
4. Kakudo K, Bai Y, Ozaki T, Homma K, Ito Y and Miyauchi A: Intrathyroid epithelial thymoma (ITET) and carcinoma showing thymus-like differentiation (CASTLE). CD5-positive neoplasms mimicking squamous cell carcinoma of the thyroid. Histol Histopathol, 28: 543-556, 2013.

論文2、3を投稿したJ Basic & Clin MedはOpen Access Journalですので、以下のURL:　 http://sspublications.org/index.php/JBCM/index　から見ることができます。この雑誌は和歌山医大と山東大学の最初の留学生単良先生（アメリカNIH職員）が始めた雑誌です。1号には山東大学孔先生、楊先生の論文が掲載されています。2号は私どもから3編（もう1編は中村美砂先生）が掲載されています。 著書としては eBook として、 ‘Clinical Management of Thyroid Cancer’の1章Z Liu, B Han, Y Bai, Y Li, O Nunobiki, K Kakudo: Borderline lesions in the thyroid tumor classification and so-called well differentiated tumor of uncertain malignant potential. Future Science Group, London, 2013.を山東大学劉先生と書きました。

日本甲状腺学会編集の甲状腺結節取扱い診療ガイドライン2013が、本年南江堂より出版の運びとなりました。2008年より5年間の歳月を費やして中村浩淑委員長のもと29名の委員が取り組みました。病理学会からは、加藤良平、亀山香織、廣川満良とわたくしが加わりました。この内容には細胞診断の診断様式が取り上げられています。日本病理学会では、6月6日札幌での甲状腺病理学会コンパニオンミーティングで取り上げました。まだまだ認知いただけるまで時間がかかりそうですので、11月大阪国際会議場で開催されます第52回日本臨床細胞学会秋期大会シンポジウムとして取り上げたいと思っています。興味のある方は是非ご参加ください。また9月26日に名古屋で開催される第46回甲状腺外科学会でも一般講演ですが、紹介したいと思っています。また、11月和歌山での甲状腺学会でも取り上げていただきたく考えています。細胞診の変更点は以下の通りです。日本甲状腺外科学会編集の「甲状腺癌取り扱い規約」に記載された米国細胞学会が推奨した細胞診断様式（パパニコロウ協会様式）に3点（１．鑑別困難を2分した。2．濾胞性腫瘍を疑う群を悪性の確率から亜分類することを推奨した。３．カテゴリーごとの悪性の確率を示した。）修正を加えたものである。甲状腺結節取り扱い診療ガイドラインでは、細胞診断に基づく臨床的対応についても記載している。日本と欧米の甲状腺癌の予後と治療方針に違いがあるため、日本独自の診療方針と治療方針との間で整合性を保つため、欧米の細胞診断様式と以下の3点で相違点が生じた。１）嚢胞性病変の取り扱い（上皮細胞が６集塊以上ない時は検体不適とするか良性と診断するか）。２）乳頭癌を疑うが、乳頭癌と断定的に診断できない病変の取り扱い（悪性疑いとするか、鑑別困難とするか）。３）濾胞性腫瘍を疑う時の取り扱い（細胞診のみを根拠として手術適応とするか、画像所見を参考に手術適応を決定するか）。

医学研究に携わって多くの論文を書いてきましたが、研究内容が地味（？）なため、また基礎研究で重箱の隅をつつく内容（？）であるため、今まであまり注目を集めることはありませんでした。また治療に直接関与していないため、患者さんから感謝の言葉をいただいたこともありませんでした。しかし、先週初めて以下のようなmailを、面識のない患者（病院名、患者名は個人情報のため伏せさせていただきます）からいただき、インターネット情報はすごい、研究論文を書くことで患者に情報を発信し、時に役に立っているのだと実感することができ喜んでいます。どのような内容の論文であるか興味のある方はhttp://onlinelibrary.wiley.com/doi/10.1111/j.1440-1827.2011.02773.x/full　をご参照ください。 Dear Dr. Kakudo, I wanted to write and thank you for publishing your comprehensive review of the literature on encapsulated thyroid tumors, and your related papers.  I am referring to Classification of thyroid follicular cell tumors: with special reference to borderline lesions (2011), and Encapsulated papillary thyroid carcinoma, follicular variant: a misnomer, (2012), which make many salient points and provide an excellent review of the literature for both professionals and interested patients. I am a patient who was diagnosed with an encapsulated, mutation-negative, non-invasive thyroid cancer in 2011 in the United States.  The pathology report read that it was an encapsulated classic PTC.  I did wonder a bit at the time whether there could be some kind of question or error about the diagnosis because the tumor did not appear to have been behaving in a way that could be construed as aggressive.  There was no spread to the nodes or outside the thyroid, molecular tests revealed no known genetic mutations and I was also tg undetectable, both basal and stimulated.  I was puzzled, and I did see while looking online that there was some kind of controversy about encapsulated FVPTC, but I was told that I didn’t have FVPTC and also that there are many cases of mutation negative thyroid cancer.  I was also told that I was “low risk” but on the advice of my endocrinologist I submitted to a treatment of radioiodine (50 mCi). Like many or even most patients, when I was diagnosed I really had very little idea of the definition of thyroid cancer according to tumor classification and how that plays into the reasoning of a given pathologist. I had no way of contextualizing “thyroid cancer” in a more meaningful way.  It seems that the hospital that I used treats classic encapsulated PTC the same as garden variety non-encapsulated PTC.  I had no idea that encapsulated PTC could be regarded as being under the same umbrella as encapsulated FVPTC until I did a Google search about it and saw your papers, which elucidate very effectively the problems of inter-observer variation among pathologists and also the questionable ascendency of PTC-N as a major diagnostic criterion.  I would even go beyond that and say that any patient with this type of thyroid tumor who has been diagnosed with cancer and who can read and understand your reports will probably come away feeling rather disturbed, or at the very least disconcerted by the implications.  A cancer diagnosis entails a considerable psychological burden even when the prognosis is good. It really surprised me to learn of the observer-dependent nature of the line between benign and malignant in certain situations.  But I guess what unnerved me the most is the realization that pathologists and other clinicians at times actually do not know with certainty the true nature of some lesions due to the limitations of current knowledge.  Yet these cases will nevertheless often be translated to the patient as definitively being cancer.  How is a patient to react when confronted with this actuality, other than by experiencing a lessening of confidence in the way in which thyroid pathology is being conducted in many hospitals and also with nagging uncertainty about whether their case has been over-treated?  I feel that I was not empowered as a patient and that more transparency is needed in medical practices as to the gaps in understanding in the current classification system, and the resultant gray zones in diagnosis which directly impact the lives of patients like me. It seems to be the case that there is a certain segment of patients who are the unwitting “poster children” of this gray zone in thyroid pathology. My case proceeded on the basis of PTC-N (FNA and pathology) alone because the molecular results were negative.  These uncertainties which have been unmasked by your reports suggest to me that a borderline category based upon degree of invasiveness is a very sensible solution until more hard data becomes available.  At least I can attest to what a difference it would have made to me personally.  Had I known of your research before I had my surgery and treatment, I may have insisted on a lobectomy and almost certainly would not have agreed to receive RAI ablation. Since I saw your papers I conferred with a second pathologist from New England about them, and he confirmed that the diagnosis of these “very low grade lesions” is subjective and sometimes even amounts to a “suggestion” from the pathologist.   I only wish that my original pathologist could have somehow conveyed this information to me. Maybe many pathologists and clinicians in the USA and elsewhere feel that their hands are tied due to legal concerns, but I think that for patients a borderline category makes very good sense and most likely will prevent overtreatment and psychological trauma.  It would have made such a difference for me in that it would have allowed for a lesser degree of treatment while preserving appropriate follow-up. Thank you again, Dr. Kakudo.