Takahiro Okamoto

Prognostic Factors and Treatment Outcomes for Anaplastic Thyroid Carcinoma: ATC Research Consortium of Japan Cohort Study of 677 Patients

BackgroundAnaplastic thyroid carcinoma (ATC) accounts for only 1 to 2% of all thyroid carcinomas, but it is one of the most lethal neoplasms in humans. To date, most findings about ATC have been derived from single-institution studies with limited numbers of cohorts. To obtain further insights into this “orphan disease,” we have established a multicenter registry, the ATC Research Consortium of Japan (ATCCJ). We analyzed prognostic factors and treatment outcomes using the large cohort database of the ATCCJ.MethodsMost of the Japanese centers involved in the treatment of thyroid cancer were invited to join the ATCCJ and have provided information on ATC patients treated between 1995 and 2008. The database includes 677 cases from 38 registered institutions. Survival curves were determined using Kaplan-Meier methods and were compared using the log-rank test. Cox’s proportional hazards model was used for multivariate analysis.ResultsClinical varieties of ATC were classified into four types: common type (nxa0=xa0547); incidental type (nxa0=xa029); anaplastic transformation at the neck (nxa0=xa095); anaplastic transformation at a distant site (nxa0=xa06). The incidental type followed by anaplastic transformation at the neck showed better outcomes than the other types. Anaplastic transformation at a distant site showed the worst outcomes. The 6-month and 1-year cause-specific survival (CSS) rates for common-type ATC were 36 and 18%, respectively. In all, 84 (15%) achieved long-term (>1xa0year) survival. Multivariate analysis identified age ≥70xa0years, presence of acute symptoms, leukocytosis (white blood cell count ≥10,000/mm3), large tumor >5xa0cm, T4b tumor, and distant metastasis as significant risk factors for lower survival. CSS rates also differed significantly depending on UICC stages, with 6-month CSSs of 60% for stage IVA, 45% for IVB, and 19% for IVC. For 36 of 69 (52%) stage IVA patients who underwent radical surgery, adjuvant therapies, including radiation therapy (RTX) and chemotherapy (CTX) did not show additional benefit statistically. Conversely, among 242 stage IVB patients, 80 (33%) underwent radical surgery. For those patients, therapies combining RTX with CTX significantly improved CSS.ConclusionsLong-term survival is possible for selected patients with ATC. To determine the treatment strategy, UICC stage (disease extent) and other prognostic factors (e.g., biologic malignancy grade) should be considered.

Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database

Objectiveu2002 Multiple endocrine neoplasia type 1 (MEN1) is less well recognized in Asian countries, including Japan, than in the West. The clinical features and optimal management of MEN1 have yet to be clarified in Japan. The aim of this study was to clarify the clinical features of Japanese patients with MEN1.

Revisiting the Guidelines Issued by the Japanese Society of Thyroid Surgeons and Japan Association of Endocrine Surgeons: A Gradual Move Towards Consensus Between Japanese and Western Practice in the Management of Thyroid Carcinoma

BackgroundIn 2010, the Japanese Society of Thyroid Surgeons (JSTS) and Japanese Association of Endocrine Surgeons (JAES) established new guidelines entitled “Treatment of Thyroid Tumors.” Since then, several new studies, including those that address the treatment of differentiated thyroid carcinoma (DTC) have been published, and the DTC treatment policy not only of Japanese physicians but those in Western countries has continued to evolve.MethodsWe selected six clinical questions regarding the treatment of DTC and revisited them based on newly published data from Western countries and Japan.ResultsMore data have accumulated about treatment of low-risk papillary microcarcinoma. It has become clear that conservative treatment (observation) of low-risk papillary microcarcinoma in elderly patients is an acceptable alternative to immediate surgery. Total thyroidectomy versus hemithyroidectomy for low-risk papillary thyroid carcinoma (PTC) has become an important issue, and some publications after 2010 indicated that hemithyroidectomy is adequate for these low-risk patients. Unfortunately, no published manuscripts on prophylactic central node dissection offered good evidence regarding its indications or included a large number of patients. Also, it was not evident that prophylactic lateral node dissection improves cause-specific survival, although it might reduce lymph node recurrence especially in PTC patients with large tumors, distant metastases, or clinical central node metastases. Although completion total thyroidectomy was not recommended for minimally invasive follicular thyroid carcinoma in our guidelines, it may be better to perform it in elderly patients and those with a large tumor or extensive vascular invasion. Radioactive iodine (RAI) ablation after total thyroidectomy is still performed almost routinely in many Western institutions, although recent studies showed that ablation is not beneficial in low-risk patients. In Japan, because of legal restrictions, most patients did not undergo RAI ablation, and their prognoses are excellent.ConclusionsRecently, policy for treating DTCs has changed not only in Western countries but also in Japan, resulting in a gradual move toward consensus between Western practice and ours. We will continue to present the best treatments for patients with thyroid carcinoma each time we revise our guidelines.

High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients

OBJECTIVEnThe precise penetrance of pheochromocytoma (PHEO) in multiple endocrine neoplasia type 2 (MEN2) has not been reported in a large cohort. In this study, we aimed to clarify the codon-specific penetrance of PHEO in MEN2.nnnDESIGNnWe established a study group designated the MEN Consortium of Japan in 2008 and asked physicians and surgeons to provide clinical and genetic information on patients they had treated up to 2011.nnnMETHODSnData were collected on patients identified as carriers of the RET mutation or diagnosed with medullary thyroid carcinoma (MTC) and/or PHEO with family history from 52 institutions all over Japan.nnnRESULTSnOf 493 registered MEN2 patients, RET mutation data were available for 390. Of these, 144 developed PHEOs, while 246 did not. The penetrance of PHEO was 25% by age 30 years, 52% by age 50 years, and 88% by age 77 years in RET mutation carriers with a codon 634 mutation. All patients with a codon 918 mutation (MEN2B) developed PHEO by age 56 years. Less than 32%penetrance of PHEO was seen in patients with mutations at codons other than 634 and 918.nnnCONCLUSIONSnMost patients with a codon 634 mutation develop PHEOs as well as MTC during their lifetime.

Thymic neuroendocrine tumour in multiple endocrine neoplasia type 1: female patients are not rare exceptions

Thymic neuroendocrine tumour (Th‐NET) occurs in 2–5% of patients with MEN1 and has high malignant potency accompanying recurrence and distant metastasis. While Th‐NET is recognized to develop predominantly in men and heavy smokers, a number of female patients have been reported in the literature. The objective of this study is to clarify the clinical features of MEN1 patients with Th‐NET using database analysis.

Tyrosine-kinase inhibitors to treat radioiodine-refracted, metastatic, or recurred and progressive differentiated thyroid carcinoma [Review]

Differentiated thyroid carcinoma (DTC) is generally indolent in nature and, even though it metastasizes to distant organs, the prognosis is normally excellent. In contrast, the overall survival (OS) of patients with radioactive iodine (RAI)-refractory and progressive metastases is dire, because no effective therapies have been available to control the metastatic lesions. However, recently, administration of tyrosine-kinase inhibitors (TKIs) has become a new line of therapy for RAI-refractory and progressive metastases. Previous studies have reported significant improvement regarding the progression-free survival rates of patients with metastatic lesions. However, TKIs cause various severe adverse events (AEs) that damage patients quality of life and can even be life-threatening. Additionally, metastatic lesions may progress significantly after stopping TKI therapy. Therefore, it is difficult to determine who is a candidate for TKI therapy, as well as how and when physicians start and stop the therapy. The present review, created by Committee of pharmacological therapy for thyroid cancer of the Japanese Society of Thyroid Surgery (JSTS) and the Japan Association of Endocrine Surgeons (JAES) describes how to appropriately use TKIs by describing what we do and do not know about treatment using TKIs.

CQ28. Do Total Thyroidectomy and Lymph Node Dissection for Sporadic and Hereditary Medullary Carcinoma Improve the Prognosis

Whether the extent of thyroidectomy or the execution and the extent of lymph node dissection affect the prognosis of patients with medullary carcinoma was investigated. Hereditary and sporadic medullary carcinomas were separately investigated.

CQ29. Is Chemotherapy Effective for Advanced or Relapsed Medullary Carcinoma

We studied the literature for the effectiveness of chemotherapy on advanced or relapsed medullary thyroid carcinoma with no indications for surgery, where tangible tumors were detectable on palpation or imaging studies. Serum cacitonin level and CEA level are sensitive tumor markers of medullary carcinoma and these elevations are often initial signs of recurrence before findings on imaging studies, but no reports are available for chemotherapy for cases without relapsed tumors for which sizes can be measured.

CQ30. What Are Prognostic Factors of Medullary Carcinoma

Since serum CEA and calcitonin levels are sensitive tumor markers of medullary thyroid carcinoma, they can be used not only on the evaluation of carcinoma relapse that is manifest and tangible on physical findings and imaging studies, but also on biochemical relapses in which these laboratory data are the measure of treatment outcomes [1, 2]. The literature was surveyed regarding prognostic factors for these outcomes.

CQ26. What Is the Usefulness of RET Gene Mutation Analysis for Medullary Carcinoma

It is very important to differentiate whether a medullary carcinoma is hereditary or sporadic when determining the treatment strategy preoperatively. If hereditary, it is either multiple endocrine neoplasia type 2 (MEN 2) or familial medullary thyroid carcinoma (FMTC), which is inherited as autosomal dominants. MEN 2A manifests medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia, and MEN 2B is associated with submucosal neuroma of the tongue and/or lips, hyperextension of the extremities, marfanoid habitus, intestinal ganglioneuromatosis, and thickened corneal nerves, in addition to medullary thyroid carcinoma and pheochromocytoma. FMTC hereditarily develops only as medullary carcinoma. The utility of mutation analysis of the RET gene, which is the responsible gene for MEN 2 and FMTC, is investigated based on the literature