Pheochromocytoma (PCC) and paraganglioma (PGL) are tumors of the adrenal medulla and sympathetic and parasympathetic paraganglia. Both PCC and PGL (PPGLs) are included in neuroendocrine tumors (NETs) of dispersed neuroendocrine system. The most important issue on PPGLs for pathology has been how to differentiate malignant from benign PPGLs, and the previous articles concentrated on solving this difficult issue. However, the concept of PPGLs was dramatically changed by WHO Blue Book, 4th edition (2017), in which all PPGLs have some metastatic potential, therefore, the previous categories of benign and malignant PPGLs have been eliminated in favor of an approach based on risk stratification. This review article includes following issues; 1. historical review of PPGLs, 2. significance of Ki67 labeling index, 3. comparison of scoring system of PASS, GAPP, COPPS these were cited in WHO Tumour Classification 5^th edition (2022) with explanation of each parameter, 4. immunohistochemical approach for histopathologic diagnosis using antibodies for neuroendocrine tumors, the specific markers for catecholamine synthesis such as tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) for sympathetic PPGL and choline acetyltransferase for parasympathetic PGL, and additional markers such as GATA3 and Phox2B for both sympathetic and parasympathetic PGL. Then markers for familial PPGLs such as SDHB for SDH-deficient PPGLs, CA9 for VHL, and MAX for MAX-related PPGL, and added Algorithm for diagnosis. The other familial type of MEN type2 and NF1 are discussed by some characteristic features in histology. Finally, rare types such as ACTH-producing PPGL, and dopamine-producing PPGL are discussed.

The pituitary gland plays a central role in maintaining physiological homeostasis by secreting multiple hormones that regulate diverse body functions. Dysregulation of pituitary hormones can arise from various conditions, such as pituitary tumors and autoimmune diseases, leading to a broad spectrum of symptoms. During embryonic organogenesis, the pituitary gland originates from the oral ectoderm in close contact with the adjacent hypothalamus. This tissue interaction is essential for proper development. Although the molecular mechanisms underlying pituitary development and related disorders have been extensively studied using animal models, such as rodents and zebrafish, species-specific differences limit the translatability of these findings to humans. Moreover, the scarcity of established human pituitary cell lines has hindered the investigation of human-specific mechanisms. Recent biotechnological advances have addressed these limitations by enabling the long-term culture of human pituitary tumor tissues and in vitro generation of pituitary hormone-producing cells from human pluripotent stem cells. These emerging platforms provide powerful tools for deepening our understanding of pituitary biology and diseases. In this review, we summarize current in vitro experimental models derived from pituitary tissues and pluripotent stem cells and discussed their applications in the study of pituitary development, physiology, and related disorders.

Hypothyroidism is reported to associate with adverse pregnancy outcomes. However, there are few reports in iodine-sufficient or -excess areas. We investigated the association of hypothyroidism in early pregnancy with pregnancy outcomes in an iodine-rich area, Japan. We conducted a retrospective cohort study at a tertiary center between 2004 to 2013. The eligible participants were classified into three groups: euthyroidism, subclinical hypothyroidism (SCH), or overt hypothyroidism (OH) groups, based on their thyroid hormone levels in the first trimester of pregnancy (median 11.6 weeks, IQR 10.6–12.6). SCH and OH were defined as elevated TSH levels with normal and low FT4 levels, respectively, using cohort-specific reference ranges in early pregnancy. The primary outcomes were miscarriage, preterm birth, small for gestational age (SGA), and their composite. Multivariate logistic regression analyses and restricted cubic spline analyses fitted to the regression models were performed to analyze the association and dose-dependency. 5,366 pregnant women were classified as euthyroidism, 143 as SCH, and 21 as OH. The composite outcome was not associated with SCH (odds ratio [OR], 0.73; 95%CI, 0.41–1.31), but significantly associated with OH (OR, 3.43; 95%CI, 1.36–8.68). Preterm birth was not associated with SCH (OR, 0.69; 95%CI, 0.28–1.69), but significantly associated with OH (OR, 5.56; 95%CI, 1.98–15.63). In this Japanese single-center cohort, SCH diagnosed in the first trimester was not associated with selected adverse pregnancy outcomes; however, miscarriage risk in early pregnancy could not be adequately assessed. The restricted cubic spline models for the primary outcomes showed J-shaped association with TSH, while the dose–response analysis did not show a clear increase in risk within the reference range of FT4. SCH in early pregnancy was indicated to have no association with the adverse pregnancy outcomes in an iodine-rich area. The risk of adverse pregnancy outcomes was increased exclusively in the low FT4 range.

Current guidelines recommend a 6-month contraception period following radioactive iodine therapy (RAIT) for Graves’ disease (GD), based primarily on radiation safety considerations; however, they do not account for the post-treatment surge in thyroid-stimulating antibodies (TSAb), which poses risks for fetal and neonatal GD. This retrospective study aimed to identify factors influencing TSAb trajectories and construct a predictive model for TSAb levels at 6 months after RAIT. We analyzed 82 patients who underwent RAIT, with TSAb values standardized to the upper limit of normal (ULN) to account for different assay methods. Multivariable linear regression identified the duration of antithyroid drug and potassium iodide administration, pre-RAIT TSAb levels, changes in TSAb at 3 months (3M), fractional reduction in TW at 3M, and assay method as significant predictors of TSAb levels at 6 months (adjusted R² = 0.87). A prediction score derived from this model demonstrated excellent diagnostic performance. Receiver operating characteristic analysis yielded an area under the curve of 0.99 for predicting TSAb >3.3 ULN, corresponding to the threshold for fetal GD monitoring at approximately 20 weeks of gestation, and 0.94 for TSAb >1.0 ULN. The prediction score significantly outperformed single predictors, including baseline TSAb levels and early post-TSAb changes. In conclusion, we developed a highly accurate predictive model for TSAb levels at 6 months after RAIT by integrating early post-treatment data with pre-RAIT clinical parameters. This model enables identification of patients at risk of persistent TSAb elevation, supporting individualized counseling regarding pregnancy planning beyond the conventional 6-month contraception period.

Japan is an iodine-replete country without iodine fortification. To characterize the current iodine status and thyroid function in healthy adults, a nationwide cross-sectional observational survey was conducted between 2016 and 2023. Iodine concentration in urine (UIC), serum and scalp hair as well as serum TSH, FT4 and FT3 concentrations, thyroid antibody (ThAb), thyroid volume by sonography, dietary iodine intake by diet study and anthropometry were evaluated. A total of 2,845 adults with the mean age of 45.6 years were recruited from 20 regions across Japan. The median UIC (mUIC) was 295.0 μg/L and within the WHO’s adequacy range of iodine intake. There was a regional difference in indices of iodine status, thyroid function and prevalence of ThAb positivity throughout all of the regions. The mUIC was lowest in Tanegashima Island (169 μg/L) and highest in Fukui (943 μg/L). The highest median TSH (2.11 μIU/mL) with the lowest FT4 (1.22 ng/dL) was observed in Ishikawa, Hokuriku while the lowest TSH (1.06 μIU/mL) was in Rebun Island, Hokkaido although the median values of TSH, FT4 and FT3 were within their reference range. The prevalence of ThAb positivity was 12.6%. A significant positive correlation was observed only between mUIC and median TSH. Japanese adults consume more iodine than the average intake of other ethnic groups and there were some areas with high iodine intake. Current average iodine intake was estimated to be 400 μg per day in this study population. A large-scaled epidemiological survey is required in future.

Radioiodine-refractory (RAI-R) papillary thyroid carcinoma (PTC) with disease progression is associated with poor prognosis. This study aimed to develop a predictive nomogram for progression-free survival (PFS) in RAI-R PTC by integrating clinical, pathological, and mutational features. In this longitudinal study, 145 patients with RAI-R PTC who underwent reoperation for locoregional recurrence were followed for disease progression. A Bayesian model averaging (BMA) approach was employed to identify the optimal model for predicting PFS. Model performance was assessed using time-dependent area under the receiver operating characteristic curve (AUC), Brier scores, and calibration plots. A nomogram for PFS prediction was then developed based on parameters from the optimal model. During a median follow-up of 29.7 months, 38 patients (26.2%) experienced disease progression after reoperation. Among eight candidate variables, BMA identified an optimal model that included four key predictors: treatment response, extrathyroidal/extranodal extension, mitotic count, and coexisting BRAF^V600E and TERT promoter mutations (Dmut). The hazard ratios (95% confidence intervals) were 3.86 (1.54–9.72) for biochemical incomplete response, 9.39 (3.35–26.3) for structural incomplete response, 3.40 (1.69–6.85) for extrathyroidal/extranodal extension, 1.34 (1.13–1.58) for mitotic count, and 6.08 (2.79–13.2) for Dmut. The optimal model demonstrated strong discriminative performance and stability across time points, with AUCs (95% confidence intervals) of 0.905 (0.801–1.000), 0.919 (0.857–0.981), and 0.921 (0.861–0.981) at 12, 24, and 36 months, respectively, and showed good calibration. This study demonstrates that integrating treatment response, extrathyroidal/extranodal extension, mitotic count, and Dmut into a predictive nomogram offers a clinically relevant tool for stratifying progression risk in patients with RAI-R PTC.

Multiple thyroid cysts are commonly detected by ultrasonography, and are considered clinically insignificant. On the other hand, polycystic thyroid disease (PCTD) has been proposed as a cause of antibody-negative hypothyroidism in iodine-replete regions; however, the clinical characteristics and natural history of multiple thyroid cysts as a broader entity remain unclear. To elucidate these issues, we retrospectively reviewed 7,727 consecutive new outpatients at a high-volume thyroid center between 2013 and 2016. Multiple thyroid cysts were defined as ≥4 cysts (≥3 mm in diameter) in the absence of thyroid autoantibodies. Among all patients, 164 (2.1%) met the criteria. The mean age was 58.3 years, and 91.0% were female. At presentation, 86.6% were euthyroid, 6.1% and 6.7% had subclinical hypothyroidism and subclinical hyperthyroidism, respectively, and one patient had Graves’ disease. Thus, approximately 6% of multiple thyroid cysts may be PCTD. Forty-six patients were followed up for ≥5 years (mean 9.8 years) without iodine restriction. Thyroid function remained stable in most cases, with no significant progression to overt dysfunction and no requirement for surgical or interventional treatment. Ultrasonographic findings ranged from numerous diffuse cysts throughout the gland to several scattered or localized cysts. Some cysts remained stable, some increased, and others decreased in size in the follow-up periods. The cyst distribution patterns (diffuse versus localized) were not associated with thyroid function. Therefore, multiple thyroid cysts may generally represent benign and stable clinical entities, supporting conservative management with periodic monitoring in most patients.

Malignant transformation in multiple endocrine neoplasia type 2 (MEN2)-associated pheochromocytoma is rare, and there have been few reports of treatment with ¹³¹I-metaiodobenzylguanidine (MIBG) therapy. Here, we describe a 47-year-old woman diagnosed as having bilateral pheochromocytoma with medullary thyroid carcinoma. Genetic testing confirmed the MEN2A subtype with the pathogenic variant p.C634Y in the RET oncogene. She underwent total thyroidectomy due to medullary thyroid carcinoma with elevated calcitonin levels as high as 1,380 pg/mL, classified as pT2N0M0, stage I. Plasma noradrenaline levels were significantly elevated, and abdominal computed tomography showed bilateral tumors of up to 6 and 2 cm in the right and left adrenal glands, respectively. She underwent right adrenalectomy and left partial adrenalectomy. Pathological examination confirmed bilateral pheochromocytoma, with Ki-67 indices of 2% and 12% in the left and right adrenal tumors, respectively. Calcitonin and catecholamine levels decreased after surgery. Seven years later, elevated plasma-free normetanephrine levels along with multiple metastases in the liver, spine, and pelvis on MIBG scintigraphy were indicative of metastatic pheochromocytoma. She underwent ¹³¹I-MIBG therapy with a dose of 7.6 GBq. Despite no significant change in metastatic or left adrenal tumor size, normetanephrine levels decreased from 1,210 to 437 pg/mL, and the patient has remained stable for more than 2 years after treatment without tumor growth. The malignant potential of MEN2A-associated pheochromocytoma emphasizes the need for accurate informed consent, especially when performing partial adrenalectomy. While ¹³¹I-MIBG therapy appears promising, its efficacy requires further assessment due to the limited number of reported cases of MEN2A-associated metastatic pheochromocytoma.

Macro-thyroid-stimulating hormone (macro-TSH) is a well-recognized cause of spuriously elevated TSH results. However, its characterization still relies largely on gel filtration chromatography (GFC), which may fail to detect macro-TSH associated with unstable or low-affinity immune complexes. In particular, when second-line screening tests, such as polyethylene glycol (PEG) precipitation, strongly suggest macro-TSH but GFC shows no distinct high-molecular-weight TSH fraction, macro-TSH may be incorrectly ruled out as the source of interference. A 43-year-old woman treated with levothyroxine for subclinical hypothyroidism showed persistently elevated TSH despite high-normal free thyroxine levels and no clinical signs of hypothyroidism. PEG precipitation and Protein G treatment resulted in TSH recovery rates of 8% and 23%, respectively, indicating macro-TSH mediated by immunoglobulin G, while heterophile and assay-specific interferences were considered unlikely. GFC under neutral conditions revealed a subtly broadened TSH distribution without a distinct high-molecular-weight peak. Quantitative peak analysis showed increased full width at half maximum and area under the curve, with values approximately 1.5- to 2-fold higher than those in controls in both the initial and repeat runs, confirming significant peak broadening. Under acidic conditions, the patient’s TSH elution profile completely overlapped with those of the controls, supporting the presence of macro-TSH due to low-affinity TSH–IgG complexes. This case highlights the diagnostic challenge posed by macro-TSH, particularly in cases involving low-affinity antibody interactions. It underscores the importance of assessing the overall elution profile rather than relying solely on peak position. Recognizing such atypical presentations can prevent unnecessary thyroid hormone treatment and improve diagnostic accuracy.