A Pyroglutamate Aminopeptidase 1 Responsive Fluorescence Imaging Probe for Real-Time Rapid Differentiation between Thyroiditis and Thyroid Cancer.

Current diagnostic methods for thyroid diseases, including blood tests, ultrasound, and biopsy, always have difficulty diagnosing thyroiditis accurately, occasionally mistaking it for thyroid cancer. To address this clinical challenge, we developed Ox-PGP1, a novel fluorescent probe realizing rapid, noninvasive, and real-time diagnostic techniques. This is the first imaging tool capable of noninvasively distinguishing between thyroiditis and thyroid cancer. Ox-PGP1 was introduced as a fluorescent probe custom-built for the specific detection and quantification of pyroglutamate aminopeptidase 1 (PGP-1), a known pivotal biomarker of inflammation. Ox-PGP1 overcame the disadvantages of traditional enzyme-responsive fluorescent probes that relied on the intramolecular charge transfer (ICT) mechanism, including the issue of high background fluorescence, while offering exceptional photostability under laser irradiation. The spectral properties of Ox-PGP1 were meticulously optimized to enhance its biocompatibility. Furthermore, the low limit of detection (LOD) of Ox-PGP1 was determined to be 0.09 µg/mL, which demonstrated its remarkable sensitivity and precision. Both cellular and in vivo experiments validated the capacity of Ox-PGP1 for accurate differentiation between normal, inflammatory, and cancerous thyroid cells. Furthermore, Ox-PGP1 showed the potential to rapidly and sensitively differentiate between autoimmune thyroiditis and anaplastic thyroid carcinoma in a mouse model, achieving results in just 5 min. The successful design and application of Ox-PGP1 represent a substantial advancement in technology over traditional diagnostic approaches, potentially enabling earlier interventions for thyroid diseases.

Effect of Hashimoto's thyroiditis on the dual-energy CT quantitative parameters and performance in diagnosing metastatic cervical lymph nodes in patients with papillary thyroid cancer.

BACKGROUND: To evaluate the effect of Hashimoto's thyroiditis (HT) on dual-energy computed tomography (DECT) quantitative parameters of cervical lymph nodes (LNs) in patients with papillary thyroid cancer (PTC), and its effect on the diagnostic performance and threshold of DECT in preoperatively identifying metastatic cervical LNs. METHODS: A total of 479 LNs from 233 PTC patients were classified into four groups: HT+/LN+, HT+/LN-, HT-/LN + and HT-/LN - group. DECT quantitative parameters including iodine concentration (IC), normalized IC (NIC), effective atomic number (Zeff), and slope of the spectral Hounsfield unit curve (λHU) in the arterial phase (AP) and venous phase were compared. Receiver operating characteristic curve analyses were performed to evaluate DECT parameters' diagnostic performance in differentiating metastatic from nonmetastatic LNs in the HT - and HT + groups. RESULTS: The HT+/LN + group exhibited lower values of DECT parameters than the HT-/LN + group (all p < 0.05). Conversely, the HT+/LN - group exhibited higher values of DECT parameters than the HT-/LN - group (all p < 0.05). In the HT + group, if an AP-IC of 1.850 mg/mL was used as the threshold value, then the optimal diagnostic performance (area under the curve, 0.757; sensitivity, 69.4%; specificity, 71.0%) could be obtained. The optimal threshold value of AP-IC in the HT - group was 2.050 mg/mL. In contrast, in the HT - group, AP-NIC demonstrated the highest area under the curve of 0.988, when an optimal threshold of 0.243 was used. The optimal threshold value of AP-NIC was 0.188 in the HT + group. CONCLUSIONS: HT affected DECT quantitative parameters of LNs and subsequent the diagnostic thresholds. When using DECT to diagnose metastatic LNs in patients with PTC, whether HT is coexistent should be clarified considering the different diagnostic thresholds.

Advancements in diagnosing IgG4-related disease of the head and neck: Navigating diagnostic pitfalls.

IgG4-related disease (IgG4-RD) is an immune-mediated condition affecting nearly any organ. This review focuses on the nuances of diagnosing IgG4-RD affecting the head and neck. Salivary gland involvement, especially of the submandibular glands, often permits a definitive diagnosis on biopsy. However, elevated IgG4+ plasma cells are nonspecific and can be seen in chronic sialadenitis, lymphoma, and other mimics. Careful correlation of clinical and pathological findings is essential. Given the significant overlap with chronic sinusitis, IgG4-RD of the sinonasal region is difficult to diagnose histologically. Laryngeal and pharyngeal involvement appears rare as an isolated finding of IgG4-RD. Mastoid disease is uncommon and remains a diagnosis of exclusion. Thyroid manifestations pose challenges given unclear diagnostic criteria - Riedel's thyroiditis likely represents IgG4-RD, but the fibrosing variant of Hashimoto's thyroiditis as a form of the so-called 'IgG4-related thyroiditis' requires better characterisation. Eosinophilic angiocentric fibrosis, despite histologic similarities, only partially overlaps with IgG4-RD. This review aims to guide diagnosing IgG4-RD in the head and neck through a systematic, organ-focused discussion of the clinical context, the utility of immunostaining, histological mimics, and controversial issues that pose diagnostic pitfalls. Increased awareness of the nuances and difficulties diagnosing IgG4-RD affecting the head and neck will improve recognition of this protean disease.

Hashimoto's thyroiditis is negatively associated with lymph node metastasis in PTMC.

PURPOSE: The association between Hashimoto's thyroiditis (HT) and lymph node metastasis (LNM) of papillary thyroid microcarcinoma (PTMC) remains poorly understood. We aimed to elucidate the impact of HT on PTMC and its association with LNM. METHODS: A retrospective cohort study was conducted at a single cancer referral center. Patients diagnosed with PTMC and complete clinicopathological results between January 2013 and June 2018 were included. Propensity score matching (PSM) and logistic regression analysis were performed to evaluate the difference in LNM characteristics between patients with and without HT. RESULTS: Among the 9929 PTMC patients, 2389 (24.1%) were pathologically diagnosed with HT. After PSM using variables including age, sex, primary tumor size, central neck dissection, extrathyroidal extension (ETE), gross ETE, multifocality and bilaterality, we identified 2324 pairs of patients for analysis. Patients with HT had a significantly lower incidence of LNM in the central neck (40.9% vs 56.2%, P < 0.001) and lateral neck (11.6% vs 14.2%, P = 0.016), a lower incidence of extranodal extension (ENE) (10.1% vs 17.0%, P < 0.001), fewer positive lymph nodes (median [IQR], 0 [0 to 2] vs 1 [0 to 3], P < 0.001), and a lower lymph node ratio (median [IQR], 0.00 [0.00 to 0.15] vs 0.12 [0.00 to 0.33], P < 0.001) than those without HT. Logistic regression analysis indicated that patients with HT had a significantly reduced risk of CLNM and LLNM compared to those without HT. CONCLUSIONS: Our study indicated a negative association between HT and LNM in PTMC.

IgG4-related sclerosing thyroiditis (Riedel-Struma): a review of clinicopathological features and management.

We present a thorough review of the literature on Riedel thyroiditis (RT) with emphasis on aetiology, diagnosis and management, using the PubMed, Sinomed, and China National Knowledge Infrastructure databases. Although the exact aetiology of RT remains obscure, the histopathological features are consistent with a localized form of IgG4-related systemic disease (IgG4-RSD). Nevertheless, IgG4-RSD as a systemic fibroinflammatory disorder per se rarely affects the thyroid in the context of multiorgan manifestations. The initial diagnosis of RT is based on clinical history and imaging, but confirmation by histopathological examination is mandatory. In contrast to the historical surgical approach, glucocorticosteroid therapy is currently considered first line therapy, in line with the RT currently being viewed as a manifestation of, or analogous to, IgG4-RSD. For disease relapse, immunomodulatory agents (azathioprine, methotrexate, rituximab) can be used.

Goiter and Abdominal Mass: A Rare Presentation of Riedel's Thyroiditis.

Riedel's thyroiditis (RT) is a rare inflammatory autoimmune disease, often associated with various forms of systemic fibrosis such as sclerosing mesenteritis (SM). A woman in her late 30s presented with a diffusely enlarged firm goiter and a mesenteric mass complicated by biliary obstruction and hydronephrosis. Labs and thyroid ultrasound were consistent with autoimmune thyroiditis. Abdominal imaging demonstrated a mesenteric mass that encased mesenteric vessels and ureter. Flow cytometry and infectious workup were negative. Both thyroid and mesenteric biopsies revealed dense fibrosis with patchy lymphoplasmacytic aggregates, no evidence of carcinoma, lymphoma, or IgG4-related disease, which confirmed diagnoses of RT and SM. She improved clinically with steroids. The coincidental timing of thyroid enlargement and the mesenteric mass, and the similarity in histology suggest an association between RT and SM. Overall, the case highlights the challenges in diagnosing RT given its rarity and emphasises the importance of early treatment to prevent systemic involvement.

Immunoglobulin G4-related endocrine diseases / G4-immunglobulinnal társult endokrin betegségek

Immunoglobulin G4-related disease has become the focus of interest in recent years. The disease is characterized by inflammation of the organs involved, often with a macroscopic appearance suggestive of a tumor, elevated immuno-globulin G4 levels, immunoglobulin G4-positive plasma cell infiltration on histological examination, fibrosis, oblit-erative phlebitis, and typically a rapid therapeutic response to corticosteroids. The disease can show a variety of organ manifestations, with frequent involvement of exocrine glands. Among the endocrine organs, symptoms may appear in the thyroid gland and the pituitary gland. The criteria for immunoglobulin G4-related hypophysitis were formu-lated in 2011. Until a few years ago, a condition formerly known as Riedel's thyroiditis was identified as immuno-globulin G4-related thyroiditis. Based on the criteria system for immunoglobulin G4-related thyroid diseases pub-lished in 2021, some patients with Hashimoto's thyroiditis and Graves' disease can also be classified as immunoglobulin G4-related thyroid disease. The identification of immunoglobulin G4-related endocrine diseases and the establishment of an accurate diagnosis can modify the treatment of the patient and determine the course of the disease. Other organ manifestations should be sought in patients with immunoglobulin G4-related endocrine disease and lifelong immunological follow-up is warranted.

Immunoglobulin G4-Related Thyroid Disease: A Single-Center Experience and Literature Review.

BACKGROUND: Immunoglobulin G4 (IgG4)-related disease is an entity that can involve the thyroid gland. The spectrum of IgG4-related thyroid disease (IgG4-RTD) includes Hashimoto thyroiditis (HT) and its fibrotic variant, Riedel thyroiditis, as well as Graves' disease. The early diagnosis of IgG4-RTD is important because it is a medically treatable disease, and a delay in the diagnosis might result in unnecessary surgery. We present a case series of IgG4-RTD with a review of the literature. METHODS: We retrospectively reviewed the clinical presentation and the radiological and pathological findings of patients diagnosed with IgG4-RTD between 2017 and 2021 at a tertiary medical center in Korea. We also conducted a literature review of IgG4-RTD. RESULTS: Five patients were diagnosed with IgG4-RTD during the study period. The patients' age ranged from 31 to 76 years, and three patients were men. Most patients visited the clinic for a neck mass, and hypoechogenic nodular lesions were observed on neck ultrasonography. Three patients had IgG4 HT, and two patients had IgG4 Riedel thyroiditis. All patients developed hypothyroidism that necessitated L-thyroxine replacement. The diagnosis of IgG4-RTD was confirmed after a pathological examination of the surgical specimen in the first two cases. However, the early diagnosis was possible after a core needle biopsy in three clinically suspected patients. CONCLUSION: The diagnosis of IgG4-RTD requires clinical suspicion combined with serology and histological analyses using IgG4 immunostaining. The early diagnosis of IgG4-RTD is difficult; thus, biopsy with IgG4 immunostaining and serum IgG4 measurements will help diagnose patients suspected of having IgG4-RTD.

Could there be an association between Hashimoto's thyroiditis and demodex infestation?

BACKGROUND: Human demodex mites are parasites that live in the pilosebaceous unit and can result in the disease demodicosis. While demodicosis may occur as a primary skin disease; immunosuppression, and topical or systemic immunosuppressive treatments can cause secondary demodicosis. It is known that thyroid hormones may cause skin changes, such as xerosis, and thereby may also modulate immune responses in the skin. OBJECTIVES: The aim of this study is to investigate whether or not that the changes occurring in the skin of patients with Hashimoto's Thyroiditis (HT) predispose to demodex infestation. METHODS: Seventy-eight patients being followed for a diagnosis of HT at Kocaeli University Endocrinology Outpatient Clinic, between January 2019 and March 2020, constituted the patient group. The control group consisted of 41 patients who did not have any chronic systemic or dermatological disease and were shown to have no thyroid disease by laboratory tests. Demodex intensity in the malar regions of the patient and control groups was determined using the standardized skin surface biopsy (SSSB) method and compared with each other. RESULTS: HT patients were significantly more likely to have increased demodex density and suggestive SSSB results than the controls (p < 0.001, p = 0.012, respectively). A significant correlation was found between demodex intensity and the findings of xerosis (p = 0.010, p = 0.011) and spiny follicular papules (p = 0.008, p = 0.008) in the patient or control groups, respectively. However, a significant correlation was identified between the demodex density and the symptoms of burning-stinging (p = 0.028), and feelings of dryness (p = 0.018) roughness (p = 0.028) only in the control group. CONCLUSION: Xerotic skin and/or impaired immune responses as a result of autoimmune changes in patients with HT may lead to secondary demodicosis.

Classical Hodgkin's lymphoma masquerading as Riedel's thyroiditis.

We present the case of a 38-year-old woman with a progressively tender swelling of the thyroid gland, who was treated as Riedel's thyroiditis based on two fine needle aspirations and a core biopsy. She was later found, on partial thyroidectomy, to have nodular sclerosis classical Hodgkin's lymphoma.

Risk factors for central lymph node metastasis in papillary thyroid microcarcinoma - a retrospective study of 1433 cases from a single center.

The purpose of this retrospective study was to evaluate the clinicopathological features of papillary thyroid microcarcinoma (PTMC) and the lymph node metastasis of PTMC. We retrospectively reviewed a total of 1433 patients with PTMC. The analysis data including demographics, tumor size, multifocality, bilateral, invasion capsule and Hashimoto's thyroiditis were collected from XinJiang, China. Univariate and multivariate analyses were performed to identify the clinicopathologic predictors of central lymph node metastasis: male gender [odds ratio (OR) = 2.358, p < 0.001], age ≤ 45 years (OR = 2.302, p 6.5 mm (OR = 2.388, p < 0.001), adjacent or invasion capsule (OR = 1.750, p = 0.002), Hashimoto's thyroiditis (OR = 0.501, p < 0.001). The optimal critical value of the number of dissected lymph nodes was found to be 8.5 using ROC analysis, with a sensitivity and specificity of 41.8% and 75.5%, respectively. This study suggests that evaluation of nodal metastasis is required to guide the surgical treatment of PTMC patients.

Case Report: A Variety of Immune-Related Adverse Events Triggered by Immune Checkpoint Inhibitors in a Subject With Malignant Melanoma: Destructive Thyroiditis, Aseptic Meningitis and Isolated ACTH Deficiency.

Recently, immune checkpoint inhibitors have been drawing much attention as cancer immunotherapy, but it has been shown that various immune-related adverse events (irAEs) are induced by immune checkpoint inhibitors in various organs, which has become one of the serious issues at present. A 58-year-old Japanese male with malignant melanoma was treated with nivolumab and/or ipilimumab. During the period of treatment, he suffered from various irAEs. Firstly, about 1 month after starting nivolumab monotherapy, destructive thyroiditis was induced, and so we started replacement therapy with levothyroxine. Secondly, about 1 month after starting nivolumab and ipilimumab combination therapy, aseptic meningitis was induced. We stopped both drugs and started steroid therapy with prednisolone. Finally, about 9 months after restarting nivolumab, isolated adrenocorticotropic hormone (ACTH) deficiency was induced, and so we started replacement therapy with hydrocortisone. Taken together, we should bear in mind the possibility of a variety of irAEs when we use immune checkpoint inhibitors.

Atypical de Quervain's thyroiditis diagnosed as atypia of undetermined significance by cytology and suspicious for cancer by Afirma Genomic Sequencing Classifier.

We report a case of atypical de Quervain's thyroiditis diagnosed as atypia of undetermined significance by cytology and suspicious for cancer by Afirma Genomic Sequencing Classifier. A 71-year-old male underwent thyroid ultrasound for goiter and was found to have two American Thyroid Association (ATA) 2015 high-suspicion nodules. The larger, 2.2-cm nodule was biopsied and the cytology showed atypical follicular cells and histiocytes. The Afirma Genomic Sequencing Classifier (detecting mRNA expression profile) result was ''suspicious'' (risk of malignancy ~50%) but Afirma Xpression Atlas (detecting specific mutations) did not find mutations in BRAF V600E, RET/PTC1, or RET/PTC3. The patient saw two endocrine surgeons and two endocrinologists who each recommended hemithyroidectomy. The patient chose to monitor the nodules. A new diagnostic ultrasound performed 3 months after the first one showed that the thyroid was significantly smaller and the previously seen nodules were no longer found. Re-examination of the cellular smears confirmed that the cytological findings were also compatible with de Quervain's thyroiditis. This case illustrates that atypical de Quervain's thyroiditis should be in the differential diagnosis of thyroid nodules for cytologists, radiologists, and clinicians. Furthermore, this case demonstrates that atypical de Quervain's thyroiditis can generate false positive results of molecular tests for indeterminate thyroid nodules.

Malignancy Risk Stratification of Thyroid Nodules with Macrocalcification and Rim Calcification Based on Ultrasound Patterns.

OBJECTIVE: To determine the association of macrocalcification and rim calcification with malignancy and to stratify the malignancy risk of thyroid nodules with macrocalcification and rim calcification based on ultrasound (US) patterns. MATERIALS AND METHODS: The study included a total of 3603 consecutive nodules (≥ 1 cm) with final diagnoses. The associations of macrocalcification and rim calcification with malignancy and malignancy risk of the nodules were assessed overall and in subgroups based on the US patterns of the nodules. The malignancy risk of the thyroid nodules was categorized as high (> 50%), intermediate (upper-intermediate: > 30%, ≤ 50%; lower-intermediate: > 10%, ≤ 30%), and low (≤ 10%). RESULTS: Macrocalcification was independently associated with malignancy in all nodules and solid hypoechoic (SH) nodules (p < 0.001). Rim calcification was not associated with malignancy in all nodules (p = 0.802); however, it was independently associated with malignancy in partially cystic or isoechoic and hyperechoic (PCIH) nodules (p = 0.010). The malignancy risks of nodules with macrocalcification were classified as upper-intermediate and high in SH nodules, and as low and lower-intermediate in PCIH nodules based on suspicious US features. The malignancy risks of nodules with rim calcification were stratified as low and lower-intermediate based on suspicious US features. CONCLUSION: Macrocalcification increased the malignancy risk in all and SH nodules with or without suspicious US features, with low to high malignancy risks depending on the US patterns. Rim calcification increased the malignancy risk in PCIH nodules, with low and lower-intermediate malignancy risks based on suspicious US features. However, the role of rim calcification in risk stratification of thyroid nodules remains uncertain.

Long non­coding RNA expression profiles identify lncRNA­XLOC_I2_006631 as a potential novel blood biomarker for Hashimoto's thyroiditis.

Long non­coding RNAs (lncRNAs) have been increasingly recognized as important immune checkpoints involved in the pathogenesis of autoimmune diseases. However, the exact role of lncRNAs in Hashimoto's thyroiditis (HT) has been rarely studied. The aim of the present study was to investigate the role of lncRNAs and the potential biomarkers in HT, a total of 33 patients with HT and 32 healthy volunteers were enrolled in the present study, and five patients and five healthy controls were investigated using next generation sequencing. A total of 218 dysregulated lncRNAs, including 94 upregulated and 124 downregulated lncRNAs, were identified and examined in the peripheral blood mononuclear cells (PBMCs) from patients with HT. The majority of the lncRNAs were intergenic and exonic (66.06%). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that abnormally expressed lncRNAs were enriched in the 'NF­kB expression', in the 'TGF­ß signaling pathway' and in the 'JAK­STAT signaling pathway', which are associated with the immunopathogenic mechanisms of HT. In total, three lncRNAs (LOC729737, XLOC_I2_006631 and BC041964) were validated and had a trend identical to that detected by the sequencing results. The expression of lncRNA­XLOC_I2_006631 was upregulated and was positively correlated with the serum concentrations of anti­thyroperoxidase antibody in patients with HT. Methyl­CpG­binding protein 2 (MECP2) was identified as the potential regulatory gene of lncRNA­XLOC_I2_006631 using a prediction program. The expression of MECP2 was increased and was positively correlated with the elevated expression levels of lncRNA­XLOC_I2_006631 and anti­thyroperoxidase antibody in patients with HT. Furthermore, lncRNA­XLOC_I2_006631 was able to regulate MECP2 expression in vitro. Receiver operating characteristic curve analysis suggested that lncRNA­XLOC_I2_006631 has a potential diagnostic value. Collectively, the present results indicated the important role of dysregulated lncRNAs in HT and demonstrated that lncRNA­XLOC_I2_006631 functioned as a positive regulator of MECP2 expression, suggesting a potential mechanism. Thus, lncRNA­XLOC_I2_006631 may be used as a biomarker of HT.

Pembrolizumab Exacerbates Thyroid Diseases Shown on FDG PET/CT.

A 51-year-old woman with a history of sarcomatoid hepatocellular carcinoma, status post resection, underwent FDG PET/CT. In addition to abnormal activity elsewhere, the images showed focal activity in the isthmus of the thyroid, suggestive of malignant involvement, and diffuse mild activity in the left lobe of the thyroid, suggestive of thyroiditis. After a 10-week anti-PD-1 pembrolizumab therapy, the follow-up FDG PET/CT scan demonstrated much more intense activity in both the isthmus and the left lobe of the thyroid. Pathological examination revealed papillary thyroid cancer in the isthmus and thyroiditis in the left lobe of the thyroid.

Qualitative analysis of contrast-enhanced ultrasound in the diagnosis of small, TR3-5 benign and malignant thyroid nodules measuring ≤1 cm.

OBJECTIVE: To evaluate the performance of contrast-enhanced ultrasound in the diagnosis of small, solid, TR3-5 benign and malignant thyroid nodules (≤1 cm). METHODS: From January 2016 to March 2018, 185 thyroid nodules from 154 patients who underwent contrast enhanced ultrasound (CEUS) and fine-needle aspiration or thyroidectomy in Shanghai General Hospital were included. The χ2 test was used to compare the CEUS characteristics of benign and malignant thyroid nodules, and the CEUS features of malignant nodules assigned scores. The total score of the CEUS features and the scores of the above nodules were evaluated according to the latest 2017 version of the Thyroid Imaging Reporting and Data System (TI-RADS). The diagnostic performance of the two were compared based on the receiver operating characteristic curves generated for benign and malignant thyroid nodules. RESULTS: The degree, enhancement patterns, boundary, shape, and homogeneity of enhancement in thyroid small solid nodules were significantly different (p＜0.05). No significant differences were seen between benign and malignant thyroid nodules regarding completeness of enhancement and size of enhanced lesions (p＞0.05). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the TI-RADS classification TR5 in diagnosis of malignant nodules were 90.10%, 55.95%, 74.59%, 72.22%, and 82.46%, respectively (area under the curve [AUC]=0.738; 95% confidence interval[CI], 0.663-0.813). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the total score of CEUS qualitative analysis indicators were 86.13%, 89.29%, 87.57%, 90.63%, and 84.27% respectively (AUC = 0.916; 95% CI, 0.871-0.961). CONCLUSION: CEUS qualitative analysis is superior to TI-RADS in evaluating the diagnostic performance of small, solid thyroid nodules. Qualitative analysis of CEUS has a significantly higher specificity for diagnosis of malignant thyroid nodules than TI-RADS. ADVANCES IN KNOWLEDGE: The 2017 version of TI-RADS has recently suggested the malignant stratification of thyroid nodules by ultrasound. In this paper we applied this system and CEUS to evaluate 185 nodules and compare the results with pathological findings to access the diagnostic performance.