Immunophenotyping with high-dimensional flow cytometry identifies Treg cell subsets associated with recurrence in papillary thyroid carcinoma.

The activation of Treg cell subsets is critical for the prognosis of tumor patients; however, their heterogeneity and disease association in papillary thyroid carcinoma (PTC) need further investigation. We performed high-dimensional flow cytometry for immunophenotyping on thyroid tissues and matched peripheral blood samples from patients with multinodular goiters or PTC. We analyzed CD4+ T cell and Treg cell phenotypes and compared the recurrence-free survival of PTC patients with different Treg cell subset characteristics using TCGA. Furthermore, PTC recurrent and non-recurrent group were compared by multiplex immunohistochemistry. High-dimensional flow cytometry and bioinformatics analysis revealed an enrichment of Tregs in tumors compared with multinodular goiters and peripheral blood specimens. Moreover, effector Tregs (e-Tregs) as well as FOXP3+ non-Tregs were enriched in tumor samples, and the expression of CD39, PD-1, and CD103 increased on tumor Tregs. TCGA data analysis showed that individuals with CD39hi PD-1loCD103loe-Treghi and CD39loPD-1loCD103hie-Treghi expression patterns had a high recurrence rate. According to the multiplex immunohistochemistry and analysis, compared with non-recurrent group, the proportion of high recurrence rate effector Treg clusters (CD39+PD-1-CD103- plus CD39-PD-1-CD103+) was increased in recurrent patients. Overall, our results highlight the potential of e-Treg subsets as future immunotherapy targets for PTC recurrence.

Characterization of lesions of nutritional congenital goitre in cattle.

There are few studies that classify and characterize the morphometric and immunohistochemical features of goitre in bovine thyroid glands (TGs). We investigated 39 bovine TGs (fetuses [9], stillbirths [18], neonates [12]) born to dams with low T4 hormone levels and no iodine supplementation and 10 (fetuses [3], stillbirths [3], neonates [4]) born to dams with normal T4 levels and supplemented with iodine. Body weight (BW), TG weight (TGW), TGW:BW ratio and histological lesions were determined. The TGs were classified histopathologically as normal gland (G0), mild goitre (G1), moderate goitre (G2) or severe goitre (G3). Various morphological and morphometric parameters were calculated from microscopic images using image analysis software. Immunohistochemistry was performed to detect proliferating cell nuclear antigen (PCNA). There were significant differences in the TGW:BW ratio among groups (P <0.05): 0.3 ± 0.1 in G0, 0.5 ± 0.3 in G1, 0.8 ± 0.3 in G2 and 1.3 ± 0.7 in G3. In G0, large homogeneous follicles with eosinophilic colloid were seen. In the groups with lesions (G1, G2 and G3), heterogeneity in follicle shape and size, height and area of thyroid follicular cells, height of thyroid follicular epithelium and PCNA immunolabelling were directly related to histopathological grade, with significant differences among groups (P <0.001), gradually increasing from G1 to G3 compared with G0. The TGW:BW ratio and histological grade were positively correlated (P = 0.008).

Systemic amyloidosis with amyloid goiter: An autopsy report.

Systemic amyloidosis is a rare but potentially lethal disease characterized by amyloid accumulation in all organs. Amyloid goiter is an extremely rare pathological lesion characterized by thyroid gland enlargement with fat deposition due to local or systemic amyloidosis. A 60 s woman with rheumatoid arthritis was found unconscious on her bed and declared dead after failed cardiopulmonary resuscitation. Postmortem computed tomography showed severe enlargement of the heart and thyroid glands, suggestive of cardiac hypertrophy and thyroidism. Histological examination revealed amorphous eosinophilic deposits with parenchymal cell destruction in all organs, including the heart and thyroid gland. Abnormal amorphous deposits in the tissues were positive for amyloid A as noted upon Congo red immunohistochemical staining and birefringence microscopy, confirming systemic amyloidosis with amyloid goiter. Serum biochemical analysis revealed increased levels of C-reactive protein; anti-cyclic citrullinated peptide antibody; creatinine kinase-myoglobin binding and N-terminal pro-brain natriuretic peptide; and thyroglobulin, free triiodothyronine, and free thyroxine, indicating systemic inflammation, active rheumatoid arthritis, heart failure, and destructive hyperthyroidism, respectively. These findings suggested that the cause of death was undiagnosed heart failure due to secondary systemic amyloid A (AA) amyloidosis related to rheumatoid arthritis. In addition, destructive hyperthyroidism caused by systemic AA amyloidosis may have also been one of the causes of death as indicated by cardiac overload. To the best of our knowledge, this is the first forensic autopsy report of cardiac amyloidosis with amyloid goiter. In conclusion, this autopsy report highlights the importance of increased awareness and early intervention for severe but treatable complications of systemic amyloidosis.

Evaluation of thyroid disease and thyroid malignancy in acromegalic patients.

BACKGROUND: Differences in epidemiological data from different geographical regions have made the prevalence of thyroid disease and thyroid cancer controversial. No previous study has investigated whether thyroid disease and thyroid cancer prevalence are higher in acromegalic patients than in the general population in Türkiye. The aim of this study is to determine the prevalence of thyroid disease and thyroid cancer in acromegaly and to compare it with the control group. METHODS: A total of 129 acromegalic patients (78 female, 51 male) and 247 control group patients (151 female, 96 male) were included in the study. Pituitary size, growth hormone (GH) and insulin-like growth factor (IGF)-1 levels in all patients with acromegaly and thyroid function tests, thyroid receptor autoantibody (TRAb), thyroid scintigraphy, thyroid ultrasonography (US), fine-needle aspiration cytology (FNAC) and histopathology findings after thyroidectomy were recorded. RESULTS: Thyroid lesions were present in 93 patients (72.1%) with acromegaly. While diffuse goiter (14.7%) and multinodular goiter (MNG) (47.3%) were significantly higher, Graves' disease (4.5%) was significantly lower in the acromegaly group compared to control group. The presence of thyroid lesions and thyroid nodules was significantly higher in patients with acromegaly (odds ratio 2.766; 95% CI 2.112-4.469, P<0.001 and OR 1.955; 95% CI 1.206-3.170, P=0.007). According to gender, the prevalence of thyroid lesions, MNG and thyroid cancer was significantly higher in female patients than in the control group. Thyroid cancer prevalence was found in 7% of acromegalic patients and the prevalence of thyroid cancer in the control group was 4.5%. CONCLUSIONS: It remains controversial whether the risk of thyroid cancer is increased or not in patients with acromegaly. In this study, there is no significant difference in thyroid cancer between acromegaly and control group, but thyroid lesions are significantly more common in acromegaly. Also, more research is required to determine if thyroid lesions are more prevalent in females with acromegaly.

Clinical-laboratory and ultrasound parallels of changes in the liver and thyroid gland in diffuse toxic goiter.

Detection of liver dysfunction in patients with diffuse toxic goiter (DTG) at an early stage allows for correcting it in time with appropriate therapy; therefore, diagnosing hepatobiliary system lesions in these patients is an important medical issue. We examined 62 patients, divided into two groups depending on the duration of the disease. The first group included patients with a disease duration of up to two years, the second group - patients with a disease duration of more than two years. The study and comparison of laboratory and multiparametric ultrasound criteria of liver and thyroid dysfunction were performed. Analysis of ultrasound signs of hepatobiliary system lesions in patients in the two groups showed that they were more common in the second group. There is a correlation between the stiffness of the parenchyma of the thyroid gland and liver and the duration of the disease, the level of free thyroxine (T4f), and antibodies to thyroid-stimulating hormone receptors (ArTTG). Increased liver stiffness was more common in patients with ArTTG levels above 20 IU/ml, and the degree of F1 fibrosis was higher at T4f greater than 50 pmol/l. To assess the condition of a patient with DTG and the need to correct treatment tactics, it is advisable to use the criteria of multiparametric ultrasound examination of the hepatobiliary system and thyroid gland.

A Specific Predicting Model for Screening Skip Metastasis From Patients With Negative Central Lymph Nodes Metastasis in Papillary Thyroid Cancer.

Skip metastasis is a specific type of papillary thyroid cancer lymph node metastasis (LNM). The present study aimed to clarify the typical clinical characteristics of skip metastasis and optimize the prediction model, so as to provide a more individual treatment mode for skip metastasis. We retrospectively analyzed 1075 PTC patients with different lymph node metastasis statuses from two clinical centers. Comparisons have been made between patients with skip metastasis and other types of LNM. Univariate and multivariate analyses were performed to detect the risk factors for skip metastasis with negative LNM, and a nomogram for predicting skip metastasis was established. The rate of skip metastasis was 3.4% (37/1075). Compared with other types of LNM, significant differences showed in tumor size, upper portion location, thyroid capsular invasion, and ipsilateral nodular goiter with the central lymph node metastasis (CLNM) group, and in age and gender with the lateral lymph node metastasis (LLNM) group. Four variables were found to be significantly associated with skip metastasis and were used to construct the model: thyroid capsular invasion, multifocality, tumor size > 1 cm, and upper portion. The nomogram had good discrimination with a concordance index of 0.886 (95% confidence interval [CI], 0.823 to 0.948). In conclusion, the significant differences between skip metastasis and other types of LNM indicated that the lymph node drainage pathway of skip metastasis is different from either CLNM or LLNM. Furthermore, we established a nomogram for predicting risk of skip metastasis, which was able to effectively predict the potential risk of skip metastasis in patients without preoperative LNM clue.

Periostin expression and its supposed roles in benign and malignant thyroid nodules: an immunohistochemical study of 105 cases.

BACKGROUND: Thyroid tumors are often difficult to histopathologically diagnose, particularly follicular adenoma (FA) and follicular carcinoma (FC). Papillary carcinoma (PAC) has several histological subtypes. Periostin (PON), which is a non-collagenous extracellular matrix molecule, has been implicated in tumor invasiveness. We herein aimed to elucidate the expression status and localization of PON in thyroid tumors. METHOD: We collected 105 cases of thyroid nodules, which included cases of adenomatous goiter, FA, microcarcinoma (MIC), PAC, FC, poorly differentiated carcinoma (PDCa), and undifferentiated carcinoma (UCa), and immunohistochemically examined the PON expression patterns of these lesions. RESULTS: Stromal PON deposition was detected in PAC and MIC, particularly in the solid/sclerosing subtype, whereas FA and FC showed weak deposition on the fibrous capsule. However, the invasive and/or extracapsular regions of microinvasive FC showed quite strong PON expression. Except for it, we could not find any significant histopathological differences between FA and FC. There were no other significant histopathological differences between FA and FC. Although PDCa showed a similar PON expression pattern to PAC, UCa exhibited stromal PON deposition in its invasive portions and cytoplasmic expression in its carcinoma cells. Although there was only one case of UCa, it showed strong PON immunopositivity. PAC and MIC showed similar patterns of stromal PON deposition, particularly at the invasive front. CONCLUSIONS: PON may play a role in the invasion of thyroid carcinomas, particularly PAC and UCa, whereas it may act as a barrier to the growth of tumor cells in FA and minimally invasive FC.

The course of thyroid nodules and thyroid volume over a time period of up to 10 years: a longitudinal analysis of a population-based cohort.

OBJECTIVE: Thyroid disorders are common. Information on the long-term progression of morphologic disorders is scarce. The aim of this study was to describe the course of thyroid nodules and volume over a period of up to 10 years. DESIGN AND METHODS: Data from the population-based Study of Health in Pomerania were used for longitudinal analysis of 10 years, on average. Billing data from the Association of Statutory Health Insurance Physicians were matched to the data to exclude participants with thyroid surgery, radioiodine therapy and thyroid carcinoma. Changes in the number and size of thyroid nodules and thyroid volume were observed using ultrasound. RESULTS: A total of 1270 participants were included (53% female, median age at baseline 51 years). The proportion of subjects with at least one thyroid nodule increased from 34.9 to 47.5% after 10 years. The majority of participants had an unchanged or reduced number of nodules. About one-quarter had at least one nodule of size ≥ 1 cm. The proportion of participants with goitre increased from 35 to 37% after 10 years. Nevertheless, individual thyroid volume increased by < 1 mL (95% CI: 0.38-3.66) after adjusting for age and BMI irrespective of thyroid medication. CONCLUSION: Thyroid nodules and goitre are common. After 10 years, the number of nodules did not increase in about 70% of people. This proportion did not differ substantially when excluding people with thyroid medication. Thyroid volume increased slightly over the follow-up period. These changes do not seem clinically relevant. Our results support a more restrictive approach regarding follow-up diagnostics in asymptomatic patients with thyroid nodules or minimally enlarged thyroid.

Cytomorphologic analysis of dyshormonogenetic goiter.

Dyshormonogenetic goiter is a rare cause for congenital hypothyroidism because of the lack of enzymes needed for the synthesis of thyroid hormones. They are usually treated with hormonal treatment. Cytomorphological features can lead to misdiagnosis of malignancy. Elaboration on the cytomorphological features of dyshormonogenetic goiter is scarce, with only four case reports in the literature. We present a case of a child with dyshormonogenetic goiter, highlighting its cytological features, and common differential diagnosis. We also compared cytomorphologic features with other cases reported in the literature.

Tracheomalacia after thyroidectomy for retrosternal goitres requiring sternotomy- a myth or reality?

INTRODUCTION: Tracheomalacia after thyroidectomy is not well understood. Reports on tracheomalacia are conflicting, with some suggesting a high rate and other large cohorts in which no tracheomalacia is reported. The aim of our study was to assess the incidence and factors associated with tracheomalacia after thyroidectomy in patients with retrosternal goitres requiring sternotomy at a high-volume tertiary care referral centre. METHODS: A longitudinal cohort study was conducted from January 2011 to December 2019. All adult patients who underwent thyroidectomy with sternotomy were included. Tracheomalacia was considered when tracheal rings were soft compared with other parts (proximal or distal) of the trachea and required either tracheostomy or resection with anastomosis. The decision to perform a tracheostomy or to administer continuous or bilevel positive airway pressure postoperatively was made depending on the degree of tracheomalacia. Logistic regression analysis was used to assess factors associated with tracheomalacia. RESULTS: We evaluated 40 patients who underwent thyroidectomy with sternotomy. The mean age of our cohort was 48.7 ± 11.3 years and the population was predominantly female (67.5%). One patient required tracheal resection with anastomosis, and two patients required tracheostomy. Multivariable logistic regression analysis did not reveal any patient- or thyroid-related factor significantly associated with the development of tracheomalacia in our cohort. CONCLUSIONS: The incidence of tracheomalacia after thyroidectomy with sternotomy appears to be very low. However, the occurrence of tracheomalacia after thyroidectomy in cases of large goitre is possible and hence worrisome.

Nature and outcome of malignant goiter: a revisit.

INTRODUCTION: the aim of this retrospective study is to review patients with malignant goiter, as regards their nature, demographic characterization, clinical presentation and preoperative histopathological data. METHODS: the study focused on a period of 4 years from December 2015 to January 2019. Patients´ demographic data, clinical presentation, Intra-operative findings, Pre and postoperative histopathological staging and grading were all recorded. Postoperative follow up whether early or late were also included. RESULTS: a total of 100% (n = 65) patients underwent surgery. The female to male ratio was found to be 5:1 (48 females and 17 males). Solitary nodule was the main clinical presentation in 80% (n = 52) of cases while 20% (n = 13) were multinodular swellings. Papillary carcinoma was recorded in 80% (n = 52) of patients while in 15.4% (n =10) of patients were having follicular carcinoma. The remaining 4.6% (n = 3) suffered of lymphoma; no medullary or anaplastic tumors were reported. CONCLUSION: thyroid cancer is the most commonly encountered endocrinal malignancy at our institute. Fine Needle Aspiration Cytology (FNAC) showed a high percentage of reliability in diagnosing thyroid cancer among our series. It is recommended to adapt this technique in initial screening of goiter patients in our local setting.

CD73 expression in normal, hyperplastic, and neoplastic thyroid: a systematic evaluation revealing CD73 overexpression as a feature of papillary carcinomas.

CD73 converts AMP to adenosine, an immunosuppressive metabolite that promotes tumorigenesis. This study presents a systematic evaluation of CD73 expression in benign, hyperplastic, and neoplastic thyroid. CD73 expression was assessed by immunohistochemistry in 142 thyroid samples. CD73 was expressed in normal thyroid (3/6) and goiter (5/6), with an apical pattern and mild intensity. Apical and mild CD73 expression was also present in oncocytic cell adenomas/carcinomas (9/10; 5/8) and in follicular adenomas/carcinomas (12/18; 23/27). In contrast, papillary thyroid carcinomas featured extensive and intense CD73 staining (49/50) (vs. normal thyroid/goiter, p < 0.001). Seven of nine anaplastic carcinomas were CD73-positive with heterogeneous extensiveness of staining. Medullary and poorly differentiated carcinomas were mostly CD73-negative (1/6; 2/2). These results were corroborated by NT5E mRNA profiling. Papillary carcinomas feature enhanced CD73 protein and mRNA expression with distinct and intense staining, more pronounced in the invasive fronts of the tumors.

DNA repair proteins may differentiate papillary thyroid cancer from chronic lymphocytic thyroiditis and nodular colloidal goiter.

Malignant thyroid lesions are the most common malignancy of the endocrine glands with increasing rates in the last two decades. Papillary thyroid cancer is the most common thyroid malignancy. In our study, we aimed to quantitatively evaluate the levels of DNA repair proteins MSH2, MLH1, MGMT, which are representative blocks of patients diagnosed with papillary carcinoma, chronic thyroiditis, or colloidal goiter. Total or subtotal thyroidectomy material of 90 patients diagnosed with papillary carcinoma, nodular colloidal goiter, or chronic thyroiditis between 2009 and 2012 were retrospectively evaluated. Tissue samples obtained from paraffin blocks were stained with MGMT, MSH2, MLH1 proteins and their immunohistochemistry was evaluated. Prepared sections were examined qualitatively by an impartial pathologist and a clinician, taking into account the staining method under the trinocular light microscope. Although there was no statistically significant difference in MGMT, MSH2, MLH1, follicular cell positivity, staining intensity, and immunoreactivity values, papillary carcinoma cases showed a higher rate of follicular cell positivity, and this difference was more pronounced between papillary carcinoma and colloidal goiter. In the MSH2 follicular cell positivity evaluation, the difference between chronic thyroiditis and colloidal goiter was significant (p = 0.023). The difference between chronic thyroiditis and colloidal goiter was significant in the MSH2 staining intensity evaluation (p = 0.001). The difference between chronic thyroiditis and colloidal goiter was significant in MLH1 immunoreactivity evaluation (p = 0.012). Papillary carcinoma cases were demonstrated by nuclear staining only for MSH2 and MLH1 proteins as opposed to hyperplastic nodules. The higher levels of expression of DNA repair genes in malignant tumors compared to benign tumors are attributed to the functional activation of DNA repair genes. Further studies are needed for DNA repair proteins to be a potential test in the development and progression of thyroid cancer.

The Association of Myo-Inositol and Selenium Contrasts Cadmium-Induced Thyroid C Cell Hyperplasia and Hypertrophy in Mice.

Previous studies have demonstrated that, in addition to inducing structural changes in thyroid follicles, cadmium (Cd) increased the number of C cells. We examined the effects of myo-inositol (MI), seleno-L-methionine (Se), MI + Se, and resveratrol on C cells of mice exposed to cadmium chloride (Cd Cl2), as no data are currently available on the possible protective effects of these molecules. In contrast, we have previously shown this protective effect against CdCl2 on the thyroid follicles of mice. Ninety-eight C57 BL/6J adult male mice were divided into 14 groups of seven mice each: (i) 0.9% NaCl (vehicle; 1 ml/kg/day i.p.); (ii) Se (0.2 mg/kg/day per os); (iii) Se (0.4 mg/kg/day per os); (iv) MI (360 mg/kg/day per os); (v) Se (0.2 mg/kg/day) + MI; (vi) Se (0.4 mg/kg/day) + MI; (vii) resveratrol (20 mg/kg); (viii) CdCl2 (2 mg/kg/day i.p.) + vehicle; (ix) CdCl2 + Se (0.2 mg/kg/day); (x) CdCl2 + Se (0.4 mg/kg/day); (xi) CdCl2 + MI; (xii) CdCl2 + Se (0.2 mg/kg/day) + MI; (xiii) CdCl2 + Se (0.4 mg/kg/day) + MI; (xiv) CdCl2 + resveratrol (20 mg/kg). After 14 days, thyroids were processed for histological, immunohistochemical, and morphometric evaluation. Compared to vehicle, Cd significantly decreased follicle mean diameter, increased CT-positive cells number, area and cytoplasmic density, and caused the disappearance of TUNEL-positive C cells, namely, the disappearance of C cells undergoing apoptosis. Se at either 0.2 or 0.4 mg/kg/day failed to significantly increase follicular mean diameter, mildly decreased CT-positive cells number, area and cytoplasmic density, and was ineffective on TUNEL-positive C cells. Instead, MI alone increased significantly follicular mean diameter and TUNEL-positive cells number, and decreased significantly CT-positive cells number, area and cytoplasmic density. MI + Se 0.2 mg/kg/day or MI + Se 0.4 mg/kg/day administration improved all five indices more markedly. Indeed, follicular mean diameter and TUNEL-positive cells number increased significantly, while CT-positive cells number, area and cytoplasmic density decreased significantly. Thus, all five indices overlapped those observed in vehicle-treated mice. Resveratrol improved significantly all the considered parameters, with a magnitude comparable to that of MI alone. In conclusion, the association Myo + Se is effective in protecting the mouse thyroid from the Cd-induced hyperplasia and hypertrophy of C cells. This benefit adds to that exerted by Myo + Se on thyrocytes and testis.

Was Tiepolo's wife affected by Graves' disease?

Tiepolo (1696-1770) was an Italian Rococo painter and printmaker, and is now considered to be one of the most important members of the 18th-century Venetian school. The muse that lent her face to Cleopatra and inspired many Tiepolo's works was his beloved wife, Maria Cecilia Guardi. Because of her appearance, we cannot rule out that she suffered from Graves' disease, an autoimmune condition that is characterized by goiter, exophthalmos and restlessness.

Amyloid goiter diagnosis by ultrasound-guided fine needle aspiration performed by interventional pathologist.

Amyloid goiter (AG) (primary or secondary) is extremely rare. An abdominal fat pad core needle biopsy (CNB) is the diagnostic gold standard for secondary amyloidosis. Although CNB is useful to detect amyloid infiltration of a specific organ, fine-needle aspiration (FNA) is proven to be the best diagnostic method for thyroid disorders. Guidelines recommend an ultrasound-guided FNA (US-FNA) whenever possible. This procedure is usually performed by various interventional specialists, including pathologists, who perform the procedure in addition to validating the adequacy of the sample. We report a rare case of AG diagnosed using US-FNA performed by a pathologist in a 39-year-old patient with systemic amyloidosis. US-FNA performed by pathologists is a proven, less-invasive, and cost-effective tool that ensures acquisition of adequate specimens and reduces nondiagnostic rates of this procedure to ensure timely cytological diagnosis.

Thyroid paraganglioma: A case-based systematic review of literature.

Thyroid paragangliomas are distinctly rare primary thyroid neoplasms with nearly 75 cases reported worldwide. Due to their similar embryological origin and cytohistomorphology with other thyroid neoplasms, they may pose great diagnostic challenges for pathologists, radiologists, endocrinologists, as well as surgeons leading to unnecessary aggressive therapy. With recent advances in molecular genetics, the prognostic significance of such seemingly innocuous thyroid neoplasms has been better understood. In this manuscript, we describe such a case and present a systematic review of all reported cases till date giving an update on our current knowledge regarding their diagnostic pitfalls, pathology, and molecular genetics.