Role of Surgery in Patients with Stage IE Primary Thyroid MALT Lymphoma Staged by a Modified Classification System: The Tokyo Classification.

PURPOSES: To establish the appropriate staging system and assess the role of curative thyroidectomy alone (Surgery) vs. involved-site radiation therapy after open biopsy (OB-ISRT) in stage IE mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS: We examined the Tokyo Classification as a modified classification. This retrospective cohort study included 256 patients with thyroid MALT lymphoma; 137 underwent standard therapy (i.e., OB-ISRT) and were enrolled for the Tokyo classification. Sixty stage IE patients with the same diagnosis were examined to compare Surgery with OB-ISRT. RESULTS: Overall survival (p = 0.0092) and relapse-free survival (0.00113) were significantly better in stage IE vs. stage IIE under the Tokyo classification. No OB-ISRT and Surgery patients died, but three OB-ISRT patients relapsed. The incidence of permanent complications was 28% in OB-ISRT (mainly dry mouth) and 0% in Surgery (p = 0.027). The number of painkiller prescription days was significantly greater in OB-ISRT (p < 0.001). During follow-up, the rate of the new appearance/change of the low-density area in the thyroid gland was significantly higher in OB-ISRT (p = 0.031). CONCLUSIONS: The Tokyo classification allows an appropriate discrimination between stages IE and IIE MALT lymphoma. Surgery can provide a good prognosis in stage IE cases; it also avoids complications, shortens painful periods during treatment, and simplifies ultrasound follow-up.

Adult Thyroid Outcomes of Congenital Hypothyroidism.

Background: More than 40 years have passed since the introduction of newborn screening (NBS) for congenital hypothyroidism (CH), and many early diagnosed patients have reached adulthood. Their thyroid morphology and function have been little studied. This cross-sectional, observational study was conducted to characterize the thyroid morphology and function of adult CH patients diagnosed in the framework of NBS for CH. Methods: A total of 103 adult CH patients born after 1979 were enrolled at Ito Hospital, Tokyo, Japan, and were classified into Goiter, Normal gland, and Dysgenesis groups based on ultrasonographic findings. For 60 patients, genetic analysis was performed. Thyroid function test results and the proportion of patients with thyroid nodules were compared among the three groups and between 56 female CH patients and 168 non-CH women matched for thyrotropin levels. Results: A significantly low serum free triiodothyronine/free thyroxine ratio (0.22) was observed in the Dysgenesis group. Thyroid nodules were detected in 14.3% (8/56) of female CH patients, more frequently than in non-CH women. Thyroid nodules were detected most frequently in the Goiter group (71%, 10/14). Genetic defects were identified in 89% (8/9) of patients belonging to the Goiter group, including thyroglobulin defect (33%, 3/9), thyroid peroxidase defect (33%, 3/9), and dual oxidase 2 defect (22%, 2/9). Conclusions: Our results suggest that adults with thyroid dysgenesis on levothyroxine replacement therapy have relative triiodothyronine deficiency. Most adults with goitrous CH have genetic dyshormonogenesis. They are at high risk of developing thyroid nodules. Our findings support the current guideline recommendation that CH patients with dyshormonogenesis should undergo periodic thyroid ultrasonography.

The Relationship Between Primary Thyroid Lymphoma and Various Types of Thyroid Autoimmunity: A Retrospective Cohort Study of 498 Cases, Including 9 Cases with Graves' Disease.

Background: Primary thyroid lymphoma (PTL) is known to develop mostly in patients with Hashimoto's thyroiditis (HT), and it is rare for it to develop in patients with Graves' disease (GD). The objective of this study was to investigate the clinical features, pathological findings, and long-term outcomes of PTL patients, grouped according to the presence of GD, HT, or no autoimmune thyroid disease (AITDs). The GD group was of major interest due to limited knowledge of the relationship with PTL. Methods: In this single-center retrospective cohort study, we reviewed the medical records of all patients diagnosed with PTL between August 1979 and October 2021, and we characterized the patients according to the presence of HT, GD, or no AITDs. Pathological specimens were classified according to the World Health Organization classification. Staging was performed in accordance with the Ann Arbor classification. Results: During the 42-year period, 498 participants were diagnosed with PTL. The median age was 68 (interquartile range 61-76) years, and 221 patients were stage IE, whereas the remaining 277 patients were stage IIE. Of the PTL patients, 431 (86.6%) were diagnosed with HT, 9 (1.8%) were diagnosed with GD, and 58 (11.6%) did not have AITDs. All nine patients with GD were positive for anti-thyroglobulin antibody and/or anti-thyroid peroxidase antibody. All patients with GD were treated with anti-thyroid medication. There were no significant differences in the proportions of each subtype of PTL between the PTL patients with GD and all subjects with PTL (p = 0.51), PTL patients with HT (p = 0.51), or PTL patients without AITDs (p = 0.48). The median follow-up time was 6.2 (interquartile range 3.0-10.7) years after the diagnosis of PTL. The Kaplan-Meier curve analyses showed no significant differences in overall survival and event-free survival between PTL patients with GD and those with HT (p = 0.37), or between PTL patients with GD and those without AITDs (p = 0.43). Conclusions: The PTL was observed with HT in a majority of cases, and rarely with GD (1.8%). The proportions of each pathological subtype of PTL and the prognosis of PTL were not different between the patients with GD and those with HT or those without AITDs.

Clinical course and outcome of differentiated thyroid cancer patients with pregnancy after diagnosis of distant metastasis.

PURPOSE: There is no sufficient data about the clinical course and outcome in thyroid cancer patients who become pregnant after diagnosis of distant metastasis (DM). The current study was conducted to collect information regarding the clinical and reproductive characteristics, and outcomes in thyroid cancer patients who became pregnant after being diagnosed with DM. METHODS: Records of 125 differentiated thyroid cancer (DTC) patients with age ≤45 years at DM diagnosis who had visited Ito Hospital from January 2005 to June 2021 were retrospectively reviewed. Among those 125 patients, 28 who became pregnant after DM diagnosis were classified as pregnancy group, and the remained 97 patients were classified as comparator group. RESULTS: In pregnancy group, the median age at malignancy diagnosis, DM diagnosis, and first pregnancy after DM diagnosis was 25 years (range, 4-41 years), 27 years (range, 11-41 years), and 32 years (range, 25-45 years), respectively. Fifty-five pregnancies and 40 live births were reported. Other pregnancy outcomes were miscarriage (n = 14) and induced abortion (n = 1). The 10-year progression-free survival (PFS) rates of pregnant and comparator group were 92.1% and 74.4%, respectively (p = 0.018). The multivariate analysis showed that multiple 131I treatment was independent negative prognostic factor for PFS (p = 0.046). CONCLUSIONS: DTC patients with age ≤45 years at DM diagnosis had good survival even though they became pregnant. Our results add to the information required for counseling thyroid cancer patients who have concerns about their fertility in the future.

Thyroid MALT lymphoma: self-harm to gain potential T-cell help.

The development of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is driven by chronic inflammatory responses and acquired genetic changes. To investigate its genetic bases, we performed targeted sequencing of 93 genes in 131 MALT lymphomas including 76 from the thyroid. We found frequent deleterious mutations of TET2 (86%), CD274 (53%), TNFRSF14 (53%), and TNFAIP3 (30%) in thyroid MALT lymphoma. CD274 was also frequently deleted, together with mutation seen in 68% of cases. There was a significant association between CD274 mutation/deletion and TNFRSF14 mutation (p = 0.001). CD274 (PD-L1) and TNFRSF14 are ligands for the co-inhibitory receptor PD1 and BTLA on T-helper cells, respectively, their inactivation may free T-cell activities, promoting their help to malignant B-cells. In support of this, both the proportion of activated T-cells (CD4+CD69+/CD4+) within the proximity of malignant B-cells, and the level of transformed blasts were significantly higher in cases with CD274/TNFRSF14 genetic abnormalities than those without these changes. Both CD274 and TNFRSF14 genetic changes were significantly associated with Hashimoto's thyroiditis (p = 0.01, p = 0.04, respectively), and CD274 mutation/deletion additionally associated with increased erythrocyte sedimentation rate (p = 0.0001). In conclusion, CD274/TNFRSF14 inactivation in thyroid MALT lymphoma B-cells may deregulate their interaction with T-cells, promoting co-stimulations and impairing peripheral tolerance.

t(3;14)(p14.1;q32)/FOXP1-IGH translocation in thyroid extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).

OBJECTIVES: MALT lymphoma occurs in various organs and has several characteristic genetic aberrations. Thyroid MALT lymphoma has been reported to include t(3;14)(p14.1;q32)/FOXP1-IGH as a specific genetic aberration, but the number of studies is limited. METHOD AND RESULTS: We examined 86 thyroid lymphoma cases using fluorescence in situ hybridization (FISH) for the detection of t(3;14)/FOXP1-IGH in formalin fixed paraffin-embedded tissue (FFPE). Histopathological diagnoses of the analyzed specimen were as follows: thyroid MALT lymphoma (n = 59), DLBCL (n = 23), follicular lymphoma (n = 4), and benign lesions (n = 14) included Hashimoto's thyroiditis (n = 13) and other (n = 1). Of the 100 analyzed cases, thirty-six (36 %) thyroid lymphoma cases were positive for t(3;14)/FOXP1-IGH. Thirty-three (55.9 %) of the 59 MALT lymphoma cases were positive for t(3;14)/FOXP1-IGH. Three (13.0 %) of the 23 DLBCL cases were positive for t(3;14)/FOXP1-IGH. All 4 follicular lymphomas examined were negative for t(3;14)/FOXP1-IGH. None of the benign cases was positive for t(3;14)/FOXP1-IGH, including Hashimoto's thyroiditis (0/13) and benign tissue (0/1). CONCLUSIONS: Our study found that t(3;14)/FOXP1-IGH was frequently found in thyroid MALT lymphoma. A detection of t(3;14)/FOXP1-IGH is extremely useful for the differential diagnosis between primary MALT lymphoma of the thyroid and other thyroid disorders.

Incidence of Neonatal Hyperthyroidism Among Newborns of Graves' Disease Patients Treated with Radioiodine Therapy.

BACKGROUND: The serum thyrotropin receptor antibody (TRAb) titers of Graves' disease (GD) patients are known to increase after radioiodine (RAI) therapy, and they can remain high for years. The incidence of neonatal hyperthyroidism (NH) among newborns of mothers with GD who conceived after RAI therapy has not been previously reported. The aims of this study were to investigate the incidence of NH among newborns of mothers who conceived within two years after RAI therapy, and to identify predictors of NH. METHODS: GD patients (n = 145) who conceived within two years after RAI therapy were retrospectively reviewed, and information regarding their newborns was collected. RESULTS: Of the 145 pregnant women, 54 (37%) were treated with antithyroid drugs or potassium iodide for maternal hyperthyroidism during the first trimester. There were eight newborns with NH, resulting in an incidence of 5.5%. Seven of the eight mothers whose newborns had NH were treated with antithyroid drugs or potassium iodide during their pregnancy. The incidence of NH among the newborns of mothers who conceived within 6-12 months after RAI therapy was 8.8%, within 12-18 months was 5.5%, and within 18-24 months was 3.6%. Multivariate analysis revealed that the TRAb values in the third trimester were the only risk factor for NH. The cutoff TRAb value in the third trimester for predicting NH was 9.7 IU/L (reference value <2.0 IU/L). CONCLUSIONS: The incidence of NH among newborns of mothers who conceived within two years after RAI therapy was 5.5%. The fetuses of pregnant GD patients whose TRAb value is high in the third trimester should be carefully followed by an obstetrician during pregnancy, and the newborns should be carefully followed by a pediatrician after birth.

Long-Term Outcomes of 107 Cases of Primary Thyroid Mucosa-Associated Lymphoid Tissue Lymphoma at a Single Medical Institution in Japan.

Context: Thyroid mucosa-associated lymphoid tissue (MALT) lymphoma is a type of extranodal lymphoma with a favorable prognosis. Objective: To provide information on long-term outcomes that would facilitate establishment of the optimal management strategy for thyroid lymphoma. Design, Setting, and Participants: Medical records of 107 patients (median age 67 years, 20 males, 87 females) who were diagnosed with localized thyroid MALT lymphoma stage IE or IIE at Ito Hospital were retrospectively reviewed. Main Outcome Measure: Overall and event-free survival (EFS). Results: Initial treatments included radiation therapy (RT) alone (n = 58), combined modality therapy (CMT) (n = 48), or chemotherapy alone (n = 1). All 107 patients responded to the treatment, six of whom experienced relapse. Only one patient died of lymphoma. The 5-year overall survival (OS) and EFS rates were 94% [95% confidence interval (CI), 87% to 97%] and 92% (95% CI, 85% to 95%), respectively, and the 10-year OS and EFS rates were 91% (95% CI, 83% to 95%) and 84% (95% CI, 74% to 90%), respectively. Of the 106 patients with information available on adverse events, 71 patients (67%) developed hypothyroidism after primary thyroid lymphoma treatment. The CMT group showed additional chemotherapy-induced adverse reactions in the form of neutropenia, neuropathy, constipation, and pneumonia. The 5-year OS rates of patients treated with CMT and RT were 93% (95% CI, 81% to 98%) and 94% (95% CI, 84% to 98%), respectively. Conclusions: Long-term outcomes of localized thyroid MALT lymphoma are favorable with all initial treatment modalities.

Radioiodine-Associated Exacerbation of Graves' Orbitopathy in the Japanese Population: Randomized Prospective Study.

CONTEXT: Exacerbation of Graves' orbitopathy (GO) after radioiodine (RAI) therapy has been examined in some populations but has not been fully described in Japanese populations. OBJECTIVE: The purpose of this study was to clarify the characteristics of GO exacerbation after RAI therapy and the effectiveness of low-dose prophylactic corticosteroid (PCS). DESIGN AND SETTING: This was a prospective randomized study in Tokyo, Japan. PATIENTS: Between June 2011 and June 2012, 295 patients with Graves' disease with either inactive GO or no GO received RAI therapy. Of these, 147 received no PCS (PCS-Off group), whereas 148 received low-dose PCS (starting dose, 15 mg/day of prednisolone) for 6 weeks (PCS-On group). We used magnetic resonance imaging to thoroughly evaluate GO before and 1 year after RAI therapy. MAIN OUTCOME MEASURES: Outcomes of GO 1 year after RAI therapy were determined. RESULTS: GO exacerbation occurred in 29 patients (9.8%), and only 7 patients (2.4%) required ophthalmic treatment. No significant difference in the frequency of GO exacerbation was seen between the groups (PCS-On group: n = 18 [12.1%]; PCS-Off group: n = 11 [7.5%]; P = .17). Significant prognostic factors were identified as thyroid-stimulating antibody (by 100% linear increase: risk ratio, 1.15; 95% confidence interval, 1.07-1.24; P = .0003) and clinical activity score (≥1 vs 0: risk ratio, 6.40; 95% confidence interval, 2.17-19.7; P = .0009). CONCLUSION: Exacerbation of GO after RAI therapy in the Japanese population appears less common than in other populations. Low-dose PCS did not produce a significant preventive effect and appeared insufficient. Patients presenting with risk factors would thus be recommended to receive higher-dose PCS.

Serum human chorionic gonadotropin levels and thyroid hormone levels in gestational transient thyrotoxicosis: Is the serum hCG level useful for differentiating between active Graves' disease and GTT?

Gestational transient thyrotoxicosis (GTT) is defined as transient thyrotoxicosis caused by the stimulating effect of human chorionic gonadotropin (hCG) during pregnancy. We attempted to identify the serum hCG level that causes GTT, and we compared the serum hCG levels and thyroid hormone levels of GTT patients according to whether they had a background of thyroid disease. We also evaluated serum hCG as a parameter for differentiating between active Graves' disease (GD) and GTT. We reviewed the 135 cases of pregnant women who came to our hospital to be evaluated for thyrotoxicosis during their 7th to 14th week of pregnancy, and their serum hCG level was measured at that time. Among the 135 pregnant women with thyrotoxicosis; 103 of the women had GTT, and the other 32 women had active GD. There were no correlations between their serum hCG levels and free thyroid hormone levels. There were no significant differences in thyroid hormone levels or hCG levels among the GTT groups with different thyroid disease backgrounds; i.e., the GTT group without thyroid disease, GTT group with chronic thyroiditis, GTT group with non-functioning thyroid nodules, and GTT group with GD in remission. The serum hCG level of the GTT group was significantly higher than in the active GD group, but it was not a good parameter for differentiating between the two groups. The FT3/FT4 ratio of the active GD was significantly higher than in GTT group, and was a better parameter for differentiation.

Changes in pediatric thyroid sonograms in or nearby the Kanto region before and after the accident at the Fukushima Daiichi nuclear power plant.

Following the accident at the Fukushima Daiichi Nuclear Power Station which occurred on March 11, 2011 due to the Eastern Japan Great Earthquake (the Accident), there have been concerns over elevation of the risk of thyroid cancer among children due to internal exposure to radioactive iodine. In Fukushima Prefecture, screening of children with thyroid ultrasonography has been carried out, yielding numerous findings, suggesting a possible influence from the Accident. We report thyroid ultrasonographic findings, used by similar device at Fukushima Prefecture's study, at Ito-hospital. Of the 2721 children aged 15 or less who visited our hospital between January 2005 and March 2013, 1214 children (330 boys and 884 girls; median age, 12; range of age, 4-15) were covered by evaluation of thyroid ultrasonographic findings, excluding children known in advance to have thyroid disease on the basis of disease history, palpation and blood tests. Among these 1214 children, 709 children (58.4%) were found cysts (≤ 5 mm in 665 cases) by ultrasonography, 43 children (3.5%) were found nodules (≤ 5 mm in 18 cases) and 9 children (5.2%) were found an intrathyroid ectopic thymus. Analysis of the data before and after the Accident using the same device, involving age adjustment on the basis of the standard population in 2010, showed no difference in the incidence rate of cysts or nodules. In children examined, the incidence rate of cyst formation (particularly ≤ 5 mm) was higher, and there was no difference in the incidence rate of cysts or nodules between the pre- and post-accident period.

Rituximab-including combined modality treatment for primary thyroid lymphoma: an effective regimen for elderly patients.

BACKGROUND: Primary thyroid lymphoma (PTL) develops mostly in middle-aged and older females. However, the optimal treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL), which accounts for most PTL cases, is unclear. Rituximab is a promising drug that, in combination with traditional combination therapy, has demonstrated an increased antitumor effect without a substantial increase in toxicity. In this study, treatment outcomes of elderly patients with thyroid DLBCL who underwent rituximab-including combination therapy were analyzed. METHOD: Between January 2005 and December 2011, 43 patients 60 years of age or older (median 71 years, range 60-80 years) were diagnosed as having stage IE (n=12) or stage IIE (n=31) DLBCL, and three courses of R-CHOP therapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, adriamycin 40 mg/m2, vincristine 1.4 mg/m2, and prednisolone 100 mg/body) and involved field irradiation were planned. Treatment outcomes of these patients were retrospectively reviewed. RESULTS: Two patients terminated the treatment because of interstitial pneumonia during R-CHOP therapy. Only one patient showed treatment resistance and the regimen was changed; 42 patients (98%) responded to the treatment. Five-year overall survival and event-free survival were 87% (95% confidence interval [95% CI], 64-96%) and 74% (95% CI, 50-89%), respectively. CONCLUSION: The results of the present study indicate that rituximab-including combination therapy was effective for elderly patients with thyroid DLBCL. A multicenter, long-term observational study is needed to confirm this, and additional refinement of the treatment protocol is required to optimize the antitumor effect.

Identification of independent susceptible and protective HLA alleles in Japanese autoimmune thyroid disease and their epistasis.

BACKGROUND: Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto thyroiditis (HT), which partially share immunological features. Determining the genetic basis that distinguishes GD and HT is a key to understanding the differences between these 2 related diseases. AIM: The aims of this study were to identify HLA antigens that can explain the immunopathological difference between GD and HT and to elucidate epistatic interactions between protective and susceptible HLA alleles, which can delineate the distinct function of HLA in AITD etiology. DESIGN: We genotyped 991 patients with AITD (547 patients with GD and 444 patients with HT) and 481 control subjects at the HLA-A, HLA-C, HLA-B, DRB1, DQB1, and DPB1 loci. A direct comparison of HLA antigen frequencies between GD and HT was performed. We further analyzed an epistatic interaction between the susceptible and protective HLA alleles in the development of GD and HT. RESULTS: We identified 4 and 2 susceptible HLA molecules primarily associated with GD and HT, respectively, HLA-B*35:01, HLA-B*46:01, HLA-DRB1*14:03, and HLA-DPB1*05:01 for GD and HLA-A*02:07 and HLA-DRB4 for HT. In a direct comparison between GD and HT, we identified GD-specific susceptible class II molecules, HLA-DP5 (HLA-DPB1*05:01; Pc = 1.0 × 10(-9)) and HLA-DR14 (HLA-DRB*14:03; Pc = .0018). In contrast, HLA components on 3 common haplotypes in Japanese showed significant protective effects against the development of GD and HT (HLA-A*24:02-C*12:02-B*52:01-DRB1*15:02-DQB1*06:01-DPB1*09:01 and HLA-A*24:02-C*07:02-B*07:02-DRB1*01:01-DQB1*05:01-DPB1*04:02 haplotypes for GD and HLA-A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01 haplotype for GD and HT). Interestingly, the representative protective HLA, HLA-DR13 (HLA-DRB1*13:02), was epistatic to susceptible HLA-DP5 in controlling the development of GD. CONCLUSION: We show that HLA exerts a dual function, susceptibility and resistance, in controlling the development of GD and HT. We also show that the protective HLA allele is partially epistatic to the susceptible HLA allele in GD.

Antithyroid drug treatment for graves' disease in children: a long-term retrospective study at a single institution.

BACKGROUND: The management of Graves' disease (GD) in children is associated with a dilemma. Although the established initial treatment for GD in children is antithyroid drug (ATD) treatment, the remission rate in children is said to be lower than in adults, and severe propylthiouracil-induced adverse events (AEs) are an issue. Definitive treatments are effective, but they often result in permanent hypothyroidism and the need for lifelong T4 supplementation. OBJECTIVE: The objective of this study was to investigate the outcome of ATD treatment, identify significant predictors of a remission, and evaluate the AEs of ATDs in a large pediatric population of GD patients. METHODS: We retrospectively assessed the reports of 1138 children up to 18 years of age who had been newly diagnosed with GD at our institution between 1982 and 2006. Their median age at diagnosis was 16 years (range: 3-18 years), and there were 995 females and 143 males. All patients were initially treated with an ATD. Remission was defined as maintenance of euthyroidism for more than 12 months after discontinuing ATD treatment and the absence of any relapses during the follow-up period. RESULTS: Of the 1138 patients, 723 continued on ATD treatment, 271 underwent surgery or radioactive iodine therapy, and 144 dropped out. Of the 723 patients who continued on ATD treatment, ATD treatment was subsequently ongoing in 84 and was discontinued in 639 (median duration of treatment: 3.8 years; range: 0.3-24.8 years). Of the 639 patients who discontinued ATD treatment, 334 (46.2%) achieved a remission, 247 (34.2%) experienced a relapse, and 58 (8.0%) dropped out. The cumulative remission rate increased with the duration of ATD treatment up until five years. No significant predictors of a remission were identified. The overall incidences of AEs associated with methimazole and propylthiouracil were 21.4% and 18.8% respectively. There were no fatal AEs in our population. While most AEs (91.6%) occurred within the first three months of ATD treatment, 2.7% developed more than two years after the start of ATD treatment. Seven of the eight late-onset AEs were induced by propylthiouracil. CONCLUSION: Long-term ATD treatment is a useful treatment option for GD in children.

Autoantibody against WD repeat domain 1 is a novel serological biomarker for screening of thyroid neoplasia.

BACKGROUND: Thyroid nodules are common among adults, and accurate diagnosis is critical in for management decisions. Ultrasound and fine needle aspiration cytology are the most common methods to evaluate nodules, but they are not practical for screening large numbers of patients because of cost and time considerations. OBJECTIVE: The aim of this study was to isolate an autoantibody to tumour antigen, WD repeat domain 1 (WDR1), and evaluate its diagnostic sensitivity and specificity for thyroid neoplasms. PATIENTS AND METHODS: We investigated serological biomarkers in patients with thyroid carcinoma who had a poor prognosis. Using a serological analysis of recombinant cDNA expression cloning (SEREX) strategy, we isolated WDR1 and its specific autoantibody in the sera of patients with undifferentiated thyroid carcinoma (UTC). We examined using indirect ELISA, the titre of the anti-WDR1 antibody (AWA) in 54 study patients: 10 with UTC, 20 with papillary thyroid carcinoma (PTC), 17 with benign thyroid nodule (BTN), 7 with autoimmune thyroid disease (AITD), as well as 38 controls (N). RESULTS: WDR1 was ubiquitously expressed in various types of thyroid tissues. However, the titre of AWA in UTC and PTC was significantly higher than that in BTN, AITD and N (P < 0·001). No significant correlation was observed between thyroid function, serum thyroglobulin and tumour diameter. The cut-off value estimated using ROC to differentiate malignancies from others was 0·95 (sensitivity 96·7%, specificity 91·9%, AUC 0·969, P < 0·001). CONCLUSIONS: Anti-WDR1 antibody could be a novel approach for serological screening of PTC and UTC, and could be an efficient and inexpensive biomarker.

[Silent thyroiditis and subacute thyroiditis].

Silent thyroiditis and subacute thyroiditis are important causes of transient thyrotoxicosis from rapidly progressive tissue injury, followed by the release of thyroid hormone into the circulation. The most striking differences between them are severe pain and extreme tenderness in the thyroid region. Although the etiology of these diseases is not clarified, silent thyroiditis is basically occurred in autoimmune thyroiditis. The most difficult differential diagnosis of silent thyroiditis is Graves' disease. TSH receptor antibody (TRAb) is useful, but TRAb is rarely positive in silent thyroiditis. A low thyroid radioiodine uptake value is most useful in identified silent thyroiditis.

Falsely elevated thyroid hormone levels caused by anti-ruthenium interference in the Elecsys assay resembling the syndrome of inappropriate secretion of thyrotropin.

The syndrome of inappropriate secretion of thyrotropin (SITSH) is defined as the inappropriate non-suppression of serum TSH in the presence of elevated free thyroid hormone; TSH-secreting pituitary adenomas and the syndrome of resistance to thyroid hormone are the main etiologies of SITSH. In addition, erroneous thyroid function testing may result in the diagnosis of this syndrome. A 63-year-old woman was referred because of suspected SITSH. Laboratory tests showed a normal TSH (0.52 µIU/L; normal range: 0.5-5.0) measured by sandwich Elecsys, and elevated FT4 (3.8 ng/dL; normal range: 0.9-1.6) and FT3 (7.6 pg/mL; normal range: 2.3-4.0), determined by competitive Elecsys. To exclude possible assay interference, aliquots of the original samples were retested using a different method (ADVIA Centaur), which showed normal FT4 and FT3 levels. Eight hormone levels, other than thyroid function tests measured by competitive or sandwich Elecsys, were higher or lower than levels determined by an alternative analysis. Subsequent examinations, including gel filtration chromatography, suggested interference by substances against ruthenium, which reduced the excitation of ruthenium, and resulted in erroneous results. The frequency of similar cases, where the FT4 was higher than 3.2 ng/dL, in spite of a non-suppressed TSH, was examined; none of 10 such subjects appeared to have method-specific interference. Here, a patient with anti-ruthenium interference, whose initial thyroid function tests were consistent with SITSH, is presented. This type of interference should be considered when thyroid function is measured using the Elecsys technique, although the frequency of such findings is likely very low.

Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves' disease.

CONTEXT: Although antithyroid drug (ATD)-induced hematopoietic damage is a significant concern, it has not been comprehensively investigated. OBJECTIVE: Our objective was to describe the clinical features of ATD-induced hematopoietic damage. DESIGN AND SETTING: This was a retrospective cohort study in Tokyo, Japan. PATIENTS: Between January 1983 and December 2002, 50,385 patients at Ito Hospital were diagnosed with Graves' disease. We retrospectively reviewed their medical, pathological, and laboratory records between January 1983 and December 2010. MAIN OUTCOME: Incidence and clinical features of ATD-induced agranulocytosis and pancytopenia were evaluated. RESULTS: Of 55 patients with documented hematopoietic damage, 50 had agranulocytosis and 5 had pancytopenia. All of them received ATD, either methimazole (n = 51) or propylthiouracil (n = 4). Median intervals between initiation of ATD therapy and the onset of agranulocytosis and pancytopenia were 69 d (range, 11-233 d) and 41 d (range, 32-97 d), respectively. Either anemia or thrombocytopenia was also documented in seven of the 50 patients with agranulocytosis. Agranulocytosis was the first manifestation of hematopoietic damage in four of the five patents with pancytopenia. Hematopoietic damage recovered with supportive measures including granulocyte colony-stimulating factor (n = 37), steroids (n = 10), and other supportive measures (n = 8) in 54 patients, whereas the remaining patient died of complications from infection. This study failed to identify the risk factors for ATD-induced hematopoietic damage. CONCLUSIONS: This study showed that ATD cause hematopoietic changes, which are occasionally severe and potentially fatal. The pathogenesis of agranulocytosis and pancytopenia might overlap, and additional studies are warranted to clarify this and to establish an optimal treatment strategy.

Prevalence of malignant tumors and adenomatous lesions detected by ultrasonographic screening in patients with autoimmune thyroid diseases.

BACKGROUND: Thyroid ultrasonography (US) is the most sensitive method for detecting thyroid nodules, and US-guided aspiration biopsy is the most accurate diagnostic procedure for thyroid nodules. We performed this retrospective study to establish the prevalence of thyroid nodules in Graves' disease and patients with Hashimoto's thyroiditis at the time of their initial visit. METHODS: We performed thyroid US as routine screening in 1652 patients with Graves' disease and 2036 Hashimoto's thyroiditis and performed US-guided fine-needle aspiration biopsy when the diameter of a nodule >1 cm or a nodule was suspected of being malignant. RESULTS: The prevalence of papillary carcinoma in the patients with Hashimoto's thyroiditis was higher than in the patients with Graves' disease (1.77% vs. 0.97%), and two patients with Hashimoto's thyroiditis (0.098%) were found to have malignant lymphoma. Adenomatous lesions were observed more frequently in the patients with Hashimoto's thyroiditis than in the patients with Graves' disease. The prevalence of adenomatous lesions increased in an age-dependent manner in both the patients with Graves' disease and those with Hashimoto disease; and adenomatous lesions were more frequent in younger patients with Hashimoto' s thyroiditis than in those with Graves' disease. CONCLUSIONS: The prevalence of both thyroid papillary cancer and adenomatous lesions was greater in the patients with Hashimoto's thyroiditis than in those with Graves' disease; and adenomatous lesions were more frequent in younger patients with Hashimoto's thyroiditis. We recommend performing US at the time of the initial visit in patients with autoimmune thyroid disease, who have a high prevalence of thyroid papillary carcinoma, to detect malignant thyroid tumors and adenomatous lesions.

Measuring thyroglobulin autoantibodies by sensitive assay is important for assessing the presence of thyroid autoimmunity in areas with high iodine intake.

There is some debate over the clinical utility of measuring serum TgAb to assess the presence of thyroid autoimmunity. To clarify the relationship between TgAb levels and thyroid autoimmunity, a histological examination of thyroid tissue was carried out on unselected living individuals with detectable serum TgAb. 146 patients with a pathological diagnosis of follicular adenoma were selected as subjects. Focal lymphocytic infiltration (FLI) was defined as lymphocytic aggregates of more than 200 in number. A thyroid gland in which 0-1 FLI was observed in a few visual fields of low magnification (20 x 4) in thyroid tissue adjacent to a tumor was judged to be normal and a thyroid gland in which 2 or more FLI were observed was diagnosed as focal lymphocytic thyroiditis (FLT). Serum levels of TgAb and TPOAb were measured by radioimmunoassay. Out of the 146 patients, 18 had detectable serum TgAb and 16 had detectable serum TPOAb. All but one (i.e. 94%) of the 18 TgAb positive patients had FLT and 14 out of the 16 TPOAb positive patients had FLT. The sensitivity (17/32; 53.1%) and specificity (113/114; 99.1%) of TgAb for detecting FLT were higher than those (14/32; 43.7% and 112/114; 98.2%) of TPOAb, but the differences were not significant. In 9 patients who were TgAb positive (but TPOAb negative), 8 (88.9%) had FLT. These results throw doubt on the Laboratory medicine practice guidelines published in Thyroid 2003, in which measuring TgAb is not usually necessary for detecting autoimmune thyroid disease. At least measuring TgAb by sensitive assay is useful for assessing the presence of thyroid autoimmunity in Japan, an area with high iodine intakes.