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

In thyroid tumor classification by the World Health Organization published in 2004, there is no borderline (uncertain) tumors and in situ (non-invasive) carcinomas in their diagnostic schema, a missing link. These steps are essential for multi-step carcinogenesis from normal cells to clear cut malignant tumors. However, these steps remain unexplained in  many reviews and text books on thyroid carcinogenesis. My review “Borderline and precursor lesion of thyroid neoplasms: A missing link.” published in Journal of Basic and Clinical Medicine try to clarify this  missing link of thyroid tumor classification. You may find there are heterogenous thyroid lesions categolized in this mysterious area, which are possible source of confusion and observer disagreements in thyroid tumor diagnoses. Kakudoborderline2015JBCM

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.