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Background: Pediatric papillary thyroid carcinoma (PTC) is a rare malignancy, but with increasing incidence. Pediatric PTCs have distinct clinical and pathological features and even the molecular profile differs from adult PTCs. Somatic point mutations in pediatric PTCs have been previously described and studied, but complex information about fusion genes is lacking. The aim of this study was to identify different fusion genes in a large cohort of pediatric PTCs and to correlate them with clinical and pathological data of patients. Methods: The cohort consisted of 93 pediatric PTC patients (6-20 years old). DNA and RNA were extracted from fresh frozen tissue samples, followed by DNA and RNA-targeted next-generation sequencing analyses. Fusion gene-positive samples were verified by real-time polymerase chain reaction. Results: A genetic alteration was found in 72/93 (77.4%) pediatric PTC cases. In 52/93 (55.9%) pediatric PTC patients, a fusion gene was detected. Twenty different types of RET, NTRK3, ALK, NTRK1, BRAF, and MET fusions were found, of which five novel, TPR/RET, IKBKG/RET, BBIP1/RET, OPTN/BRAF, and EML4/MET, rearrangements were identified and a CUL1/BRAF rearrangement that has not been previously described in thyroid cancer. Fusion gene-positive PTCs were significantly associated with the mixture of classical and follicular variants of PTC, extrathyroidal extension, higher T classification, lymph node and distant metastases, chronic lymphocytic thyroiditis, and frequent occurrence of psammoma bodies compared with fusion gene-negative PTCs. Fusion-positive patients also received more doses of radioiodine therapy. The most common fusion genes were the RET fusions, followed by NTRK3 fusions. RET fusions were associated with more frequent lymph node and distant metastases and psammoma bodies, and NTRK3 fusions were associated with the follicular variant of PTC. Conclusions: Fusion genes were the most common genetic alterations in pediatric PTCs. Fusion gene-positive PTCs were associated with more aggressive disease than fusion gene-negative PTCs.

Background: Thyroglobulin (Tg) antibodies (TgAb) can interfere with Tg measurement and can be used as “Tg surrogate” in patients with differentiated thyroid cancer (DTC) treated with total thyroide...

The diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is a unique variant of PTC that is characterized by extensive lymphovascular invasion of tumor cells in a background of lymphocytic thyroiditis. The lymphatic emboli contain tumor cells as well as macrophages, but the recruitment of these macrophages is not well understood. The aim of this study was to determine the relationship between the expression of Decoy receptor 3 (DcR3), the recruitment of tumor-associated macrophages (TAMs), and lymphatic invasion in DSV-PTC.We retrospectively examined 14 cases of DSV-PTC using immunohistochemistry studies. The density of TAMs, lymphatic vessel density, lymphatic invasion, tumor emboli area, and DcR3 expression were assessed. Statistical analyses were performed using Fisher's exact test, unpaired t-test, and linear regression.The lymphatic tumor emboli contained a relatively higher density of TAMs than stroma and classical PTC (CPTC) areas. In addition, the number of lymphatic invasions and the size of the tumor emboli area were positively correlated with the number of M2 TAMs. A higher density of M2 TAMs was associated with older patients and larger tumor size. Moreover, DcR3 was expressed only in lymphatic tumor cells and squamous metaplastic tumor cells, but not in macrophages and CPTC. In addition, the preferential expression of DcR3 in tumors was associated with higher levels of M2 TAMs and lymphatic invasion.Despite the fact that the exact relationship between DcR3, M2 macrophages, and lymphatic invasion in DSV-PTC remains to be elucidated, our findings suggest that DcR3 expression in DSV-PTC tumor cells may promote the polarized macrophage differentiation toward the M2 phenotype. This phenomenon may further promote lymphatic invasion of DSV-PTC tumor cells.

Membranous expression of the sodium iodide symporter (NIS) is a prerequisite for iodide uptake in thyrocytes. Previous studies reported heterogeneous results on the relative frequency of staining in various pathological conditions of the thyroid. The present study aimed at determining membranous staining by using confocal laser microscopy in benign and malignant thyroid diseases, complemented in a subgroup of patients with recurrent or metastatic disease with functional findings of radioiodine uptake (RIU).There were 380 malignant thyroid tumors (145 papillary, 51 follicular, 87 Hurthle cell, and 97 undifferentiated thyroid carcinomas [UTC]), 115 benign adenomas, 62 diffuse goiters, 89 inflammatory conditions (Graves', Hashimoto, Thyroiditis deQuervain, and lymphocytic thyroiditis), and 179 normal tissues (NT, fetal, and adult). These were subjected to NIS (two different antibodies) and thyroglobulin (TG) staining and evaluated by confocal microscopy.In a subgroup of 50 samples from patients with recurrent or metastatic disease, NIS staining was correlated with the RIU. As compared with NT, Graves' patients had significantly higher positive NIS membrane staining (97% vs. 69%) whereas patients with Hashimoto, lymphocytic thyroiditis but also benign adenomas scored lower than NT (56.7% and 55.8% vs. 69%). Depending on their differentiation NIS staining was significantly lower in thyroid carcinomas in parallel with TG staining with only 1/97 UTCs being positive. RIU was more frequently detectable than NIS staining.Confocal staining strictly evaluating only membranous expression of NIS has not used on a large scale before this study. We confirm the loss of membranous NIS in benign but more prominently in malignant thyroid tumors. NIS staining of diagnostic tissues cannot be used to predict RIU.

Phosphatase and tensin homolog deleted on chromosome ten (PTEN)-hamartoma tumor syndrome (PHTS) is a complex disorder caused by germline inactivating mutations of the PTEN tumor suppressor gene. PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and Proteus-like syndromes. Affected individuals develop both benign and malignant tumors in a variety of tissues, including the thyroid. This study is to better characterize and describe the thyroid pathology within the different entities of this syndrome, and examine whether there is an association between specific thyroid findings and different PTEN mutations.Twenty patients with known PTEN mutations, and/or clinical diagnosis of PHTS, and thyroid pathology were identified: 14 with CS and 6 with BRRS.Thyroid pathology findings were as follows: multiple adenomatous nodules in a background of lymphocytic thyroiditis (LT) in 75%, papillary carcinoma in 60%, LT alone in 55%, follicular carcinoma in 45%, C-cell hyperplasia in 55%, and follicular adenomas in 25%. Within the papillary carcinoma group, there were 6 microcarcinomas, 5 follicular variants, and 1 classical type.There were no morphologic differences between the thyroid findings in CS and BRRS. Also, there was no correlation between specific PTEN germline mutations (exons 5, 6, and 8) and pathologic findings. Distinctive and characteristic findings in PHTS include multiple unique adenomatous nodules in a background of LT, and C-cell hyperplasia; it is vital that pathologists recognize the classical histologic features of this syndrome to alert clinicians to the possibility of this syndrome in their patients.

Hashimoto's thyroiditis is usually treated medically; however, thyroidectomy is sometimes indicated. Thyroiditis can make thyroid dissection more difficult and possibly increase the risk of surgical complications. The aim of this study was to determine the rate of complications and associated cancer in patients with Hashimoto's thyroiditis.Retrospective series of 474 patients treated surgically at the University of California, San Francisco, between January 1985 and June 2005 with final pathology demonstrating Hashimoto's thyroiditis, chronic lymphocytic thyroiditis, or chronic thyroiditis. Parameters evaluated included demographics, surgical indications, and postoperative complications.Among the 474 patients, 133 had thyroidectomy because of preoperative diagnosis of thyroid cancers (median age 39 years; 116 females and 17 males), 316 had thyroidectomy because of benign thyroid nodules or goiter (median age 47.5 years; 292 females and 24 males), and 25 had thyroidectomy to relieve local symptoms caused by thyroiditis but did not have thyroid nodules (median age 42 years; 25 females). No death or permanent surgical complications occurred. One hundred and fifty-two patients (32.1%) had transient postoperative hypocalcemia, 2 (0.4%) had transient recurrent nerve palsy, and 4 (0.8%) had a postoperative neck hematoma. Fifty-three percent had thyroid cancer at final histological examination.Thyroidectomy can be performed in patients with Hashimoto's thyroiditis with a low risk of permanent surgical complications. Cancer is common in patients who have a thyroidectomy for Hashimoto's thyroiditis even when not suspected preoperatively.

The familial form of nonmedullary thyroid carcinoma (FNMTC) has been recognized as a distinct clinical entity and is characterized by multifocality and a more severe phenotype than its sporadic counterpart. The majority of FNMTC pedigrees are small in size, show variable modes of inheritance, and may present with a variety of additional benign thyroid disorders. The existence of marked phenotypic differences between FNMTC families suggests that there is genetic heterogeneity. Recent studies have mapped a susceptibility locus for FNMTC at 2q21. This locus appears particular relevant to families with at least one case of the follicular variant of papillary thyroid cancer (fvPTC). We describe the clinical and pathologic characteristics of a large three-generation fPTC kindred, with two of the four PTC patients presented with the follicular variant of PTC. It is of interest the occurrence of PTC in three siblings within a period of 3 years. In addition, multinodular goiter (MNG) was diagnosed in seven individuals, lymphocytic thyroiditis in four, while one diagnosed with a benign adenoma. From the PTC patients, one had MNG and fvPTC, one MNG, lymphocytic thyroiditis and papillary pattern of PTC, one lymphocytic thyroiditis and fvPTC, and one MNG and papillary pattern of PTC. The inheritance pattern was autosomal dominant with incomplete penetrance and women were affected more frequently than men. Considering all PTC-affected individuals, the limit of detection (LOD) score we got for this family on 2q21 was 0.5. The low LOD score is caused by a PTC patient who does not share the affected haplotype, suggesting that maybe a new locus for PTC predisposition is present in this kindred. Linkage analysis also excluded TCO, MNG, and fPTC/PRN as susceptibility loci to FNMTC in this family.

Ultrasonography (US) may demonstrate a diffuse reduction in thyroid echogenicity (low-amplitude echoes) in autoimmune thyroid disease (AITD), which includes chronic lymphocytic thyroiditis and Graves' disease, as well as in subacute thyroiditis. The reported occurrence of this finding in AITD varies from 19% to 95%. To assess the validity of diffuse reduction in thyroid echogenicity as a predictor of AITD, 3,077 patients referred for US of the thyroid were examined prospectively with regard to reduced versus normal thyroid echogenicity. The most frequent reasons for referral were goiter, thyroid dysfunction, neck discomfort, and/or difficulty in swallowing. Ultrasonography demonstrated diffuse reduction in thyroid echogenicity in 485 patients. Of these, 452 patients had available records of fine-needle aspiration biopsy (FNAB), and were included in the study. From the remaining patients, with normal thyroid echogenicity, 100 consecutive patients were selected as controls. In 411 of the 452 study patients (90.9%) there was at least one laboratory finding consistent with possible AITD: cytology indicating lymphocytic thyroiditis, 287 of 363 patients (79.1%) with diagnostic specimens; elevated levels of peroxidase antibodies (TPOAb), 225 of 337 (66.8%); elevated thyrotropin (TSH) levels, 290 of 450 (64.4%); or low TSH levels, 79 of 450 (17.6%). The final diagnosis was: chronic autoimmune (Hashimoto's) thyroiditis in 352 patients; Graves' disease in 47 patients; subacute (granulomatous) thyroiditis in 7 patients; toxic nodular goiter in 3 patients; and toxic adenoma in 2 patients. In the remaining 41 patients, those without laboratory results consistent with AITD, the final diagnosis was colloid goiter in 37 and thyroid cancer in 4 patients. In the 100 controls, laboratory results were consistent with possible AITD in 14 patients: elevated TPOAb levels in 5 of 49 patients with retrieved antibody results; lymphocytic thyroiditis in 2 patients; elevated TSH levels in 2 patients; and low TSH levels in 2 patients. In these controls, the final diagnosis was: chronic autoimmune thyroiditis in 7; toxic nodular goiter in 6 patients, and toxic adenoma in 1 patient. The corresponding positive and negative predictive values of reduced thyroid echogenicity as an indicator of AITD were 399 of 452 (88.3% [95% CI, 85% to 91%]), and 93 of 100 (93.0% [95% CI, 88% to 98%]), respectively. Thus, diffuse reduction in thyroid echogenicity was a valid predictor of AITD.

Thyroid lymphomas are rare diseases and almost always rise in the background of chronic lymphocytic thyroiditis (Hashimoto's thyroiditis). Large cell lymphoma is an aggressive disease and usually is not a significant diagnostic challenge from the pathological point of view. Small cell lymphoma, however, can sometimes be difficult to distinguish from chronic lymphocytic thyroiditis. In the past, most thyroid lymphomas were considered to be of follicle center cell origin. Today, after the introduction of the mucosa-associated lymphoid tissue (MALT) and the extranodal lymphoid tissue (ELT) concepts, most of the lymphomas in the extranodal sites are thought to originate from the marginal zone of the lymphoid follicles. The distinction between the different types of lymphomas has significant impact on the patient's prognosis, treatment, and follow-up. It is imperative that clinicians (endocrinologists and surgeons) and pathologists are aware of these types of lymphomas in order for the most appropriate diagnostic procedures to be selected, specific staging principles to be applied, and appropriate disease-specific treatment to be implemented. It is also important that terms such as "lesion of uncertain malignant potential" as defined by ancillary studies be understood.

The intrathyroidal cytokine gene expression in human autoimmune thyroid disease is difficult to interpret because surgical specimens mostly reflect the autoimmune disease at a late stage. Because it is not possible to investigate early stages of thyroiditis in humans, the Bio Breeding/Worcester (BB/W) rat was used as a model. To characterize the lymphocytic thyroiditis (LT) of BB/W rats further and to evaluate early increases of cytokine gene expression in LT, we investigated the interleukin (IL)-2, -4, -6, -10, -12p40, interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) gene expression in the thyroids, spleens, and livers of BB/W rats with and without histological evidence for thyroiditis. The gene expression of these cytokines was determined by Genescan (PE Applied Biosystems, Foster City, CA) fragment analysis using reverse polymerase chain reaction (RT-PCR). Serum thyroglobulin (Tg) antibody concentrations were measured and the extent of lymphocytic infiltration of one thyroid lobe was histologically graded. Cytokine gene expression in rats with and without LT was compared in three groups of rats: 55-day-old rats after 24 days of iodine administration, 75-day-old rats after 45 days of iodine administration, and 101-day-old rats. In the thyroids of the BB/W rats no expression of IL-4 or IL-10 was detectable. The number of rats with detectable TNF-alpha, IFN-gamma, IL-2, IL-12p40 gene expression was significantly higher in rats with LT. Rats with LT had significantly higher IL-12p40 mRNA levels. There were no significant differences in the IL-6 gene expression between rats with and without LT. A correlation between the level of lymphocytic infiltration and the TNF-alpha (r = 0.56, p < 0.0065) and TG antibody concentration (r = 0.62, p < 0.0065) was found. Therefore, the early cytokine gene expression in the BB/W rat is characterized by Th1-related cytokines like IL-2 and IFN-gamma. Whether the detected IL-12p40 (10 rats) and IFN-gamma (5 rats) gene expression in animals without LT is an early indicator for the development of LT remains to be determined.