Messages from Kennichi Kakudo, MD, PhD to a person to be an expert of the cytopathology

Dear Dr. Kakudo:

I read with great personal interest your paper published in Pathology International in 2012 on the subject of encapsulated papillary thyroid cancer, follicular variant. I was wondering if I could get some advice from you?

I have recently been diagnosed to have a single follicular variant of PTC (2.3 cm), encapsulated, no capsular or lymphovascular invasion, no extra thyroidal extension and the surgical margins are negative for tumor. It has been removed surgically through lobectomy.

Is it a standard practice that encapsulation is determined at the gross examination instead of microscopy level for FVPTC, and that encapsulation is correlated with less aggressiveness of the tumor? I heard that in Japan, encapsulated FVPTC with no capsular and lymphovascular invasion would be classified as benign/borderline lesion and would only need lobectomy instead of TT+RAI?

Thanks a lot in advance for your advice.

Warm Regards,

XXXX

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Dear XXXX

Thank you for your second opinion consultation on your thyroid tumor. The followings are my answers on your questions and advices to you. Thank you. Ken

Kennichi Kakudo, MD, PhD:

Department of Pathology, Nara Hospital,

Kinki University Faculty of Medicine,

Otoda-cho, 1248-1, Ikoma-city, Nara, 630-0293, Japan,

E-mail:kakudo@thyroid.jp

“Is it a standard practice that encapsulation is determined at the gross examination instead of microscopy level for FVPTC?”

It is decided with light microscopic level after gross examination. It is because some of the invasion negative cases at gross examination turned out to be invasive at microscopic level. Therefore we confirm it with microscopic level.

“Encapsulation is correlated with less aggressiveness of the tumor?”

This was first documented in follicular thyroid carcinoma by a surgeon van Heerden from Mayo Clinic, (Follicular thyroid carcinoma with capsular invasion alone: a nonthreatening malignancy. Surgery, 112:1130-1136, 1992). It is believed that encapsulation and expansive growth are histological indicators to have a better prognosis than infiltrative growth.

It was first reported in follicular variant papillary thyroid carcinoma, by Dr Liu from SKCC in New York (Follicular variant of papillary thyroid carcinoma: a clinicopathologic study of a problematic entity, Cancer 107:1255-1264.) In their paper, non-invasive and encapsulated follicular variant papillary thyroid carcinoma has no metastasis and no recurrence (that is a benign tumor biologically). It was confirmed by our group (Liu Z et al: Encapsulated follicular thyroid tumor with equivocal nuclear change, so-called well-differentiated tumor of uncertain malignant potential: a morphological, immunohistochemical, and molecular appraisal. Cancer Sci 102: 288-289, 2011.)

“I heard that in Japan, encapsulated FVPTC with no capsular and lymphovascular invasion would be classified as benign/borderline lesion and would only need lobectomy instead of TT+RAI?”

All pathologists in the world, including US and Japanese pathologists, follow the WHO classification and all tumors with papillary thyroid carcinoma- type nuclear features (PTC-type NF) are papillary thyroid carcinomas. However threshold of PTC-type NF is different among pathologists and most of the Japanese pathologists apply stricter criteria than US pathologists. As a results, majority of follicular variant of PTC, encapsulated and non-invasive form (EnFVPTC) in US become benign follicular adenoma in Japan. It was clearly shown in our previous observer variation studies (Kakudo K et al: Thyroid gland: international case conference. Endocr Pathol 13:131-134, 2002. Hirokawa M et al: Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Patrhol 26:1508-1514, 2002.) From these studies, it was found that US pathologists made more malignant diagnoses on encapsulated non-invasive follicular pattern lesions than Japanese pathologists did.

My advices to you are as follows;

Your thyroid tumor is not biologically malignant and is cured with current surgery at more than 99.5% of probability.  No immediate actions are necessary for your treatment at this moment. We have examined 109 cases of EnFVPTC with 24 world expert thyroid pathologists and had a working group discussion in Boston on 20^th and 21^st of March, 2015, which was conducted by Professor Yuri Nikiforov, University of Pittsburgh. We confirmed no metastasis and recurrence in these 109 cases with more than 14 years follow up study.  Cancer terminology in EnFVPTC was abandoned and a new terminology, NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) was given to this tumor entity. We are working to publish it and I believe it will be published soon. In this paper, we propose it to be a precursor lesion of invasive FVPTC and biologically benign tumor. We will recommend that no further treatments are necessary to this tumor, such as so-called completion of total thyroidectomy and additional RAI treatments. Please wait until it be published and bring it to your clinical doctors for your treatment. I believe they will advise you differently from this new evidences.

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Dr. Kakudo:

Thank you for your quick and thoughtful reply; I am truly grateful. By the way, did these 109 patients all receive lobectomy? Thanks. XXXX

Dear XXXX:

They were treated in 4 different medical centers and were treated with different manners, either lobectomy alone, lobectomy + isthmectomy or total thyroidectomy. I do not remember exactly about how much those proportions among the 109 cases were. All cases were not treated with RAI. That is the main point, because RAI treatment has significant side effects and risk of second primary malignancy. I hope this massage helps you. Thank you.   Ken

PS: The other half of thyroid is essential for your thyroid function and you have  more than 50% chance of normal thyroid function. Although it may have another malignancy and multiple primary lesions of thyroid cancer are rather common, total thyroidectomy creates 100% permanent hypothyroidisms. It is not serious if you take thyroid hormone properly life-long. When you become old and unable to do this by yourself, inappropriate thyroid hormone becomes a risk of your early death due to sclerosis of coronary arteries.

As pointed out by many authors, observer disagreements between benign and malignant often occur in diagnoses of encapsulated thyroid tumor with incomplete papillary carcinoma type nuclear features (PTC-N) (Kakudo K et al. Encapsulated papillary thyroid carcinoma, follicular variant: a misnomer. Pathol Int. 62(3):155-160, 2012. Review.). These tumors are indolent and usually do not create any harm to the patients, but the malignant diagnosis may create overtreatments to the patients when the clinical doctors did not aware the indolent nature of the tumor. Particularly in US, the patients with PTC, either common type or follicular variant, with or without capsulation, with or without invasive growth and with or without metastasis, are treated with total thyroidectomy followed by radio-active iodine (RAI) treatment. (Please refer Letter from a USA patient in my HP) I believe many of the patients with encapsulated non-invasive follicular variant PTC in Western countries were treated with completion of total thyroidectomy followed by RAI treatment. To stop this overtreatment to the indolent tumors, many authors published their opinions how to prevent overtreatment (Luster M et al: Differentiated thyroid cancer-personalized therapies to prevent overtreatment. Nat Rev Endocrinol 10:563-574, 2014 and Esserman LJ et al: Addressing overdiagnosis and overtreatment in cancer: a prescription for change. Lancet Oncol, 15:e234-242, 2014)

To solve this diagnostic issue, A Working Group for Re-examination of the Encapsulated Follicular Variant of Papillary Thyroid Cancer was organized in 2014. The mission of this working group is to establish a histopathologic criteria of encapsulated non-invasive follicular variant PTC and find a new name more suitable for indolent nature of this tumor. Patients with this tumor are also invited to the meeting at USCAP symposium. We are going to see a happy end of this diagnostic issue soon, and I hope this solution will help prevent overtreatment to the patient with encapsulated thyroid tumor with PTC-N in the future.

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.

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.