Mutations of the BRAF gene in papillary thyroid carcinoma and in Hashimoto's thyroiditis

The purpose of the present study was to investigate the frequency of BRAF mutations in human papillary thyroid carcinoma (PTC) and Hashimoto's thyroiditis (HT) and to evaluate the association of the BRAF mutation with the clinicopathological features of both of these thyroid disorders. A total of 51 PTC with no HT, 28 PTC with HT and 27 HT with no PTC were evaluated using DNA extracted from paraffin-embedded specimens. BRAF mutations were analyzed by direct DNA sequencing of the polymerase chain reaction (PCR)-amplified exon 15. The BRAF missense mutation at codon 599 (T1796A) was present in 46 of 51 PTC (90%) with no HT, 18 of 28 PTC (64%) with HT, four of 28 HT (14%) with PTC, and zero of 27 HT with no PTC. The BRAF mutation at codon 600 (A1798G) was not detected in any case. Clinicopathological examination of 106 patients with either PTC or HT showed that the BRAF mutation was significantly correlated with patient age. These data indicate that the BRAF mutation is associated with a valuable biological property of PTC and may participate in the pathogenesis of PTC arising in HT. These results indicate that the detection of the BRAF mutation in HT can be helpful for prediction of progress to PTC.     

Hashimoto's thyroiditis with papillary thyroid carcinoma (PTC)-like nuclear alterations express molecular markers of PTC

AIMS: Focal papillary thyroid carcinoma (PTC)-like nuclear alterations have been documented in Hashimoto's thyroiditis; however, the molecular association between PTC and Hashimoto's thyroiditis is poorly understood. The aim of this study was to determine whether molecular expression patterns of PTC are present in association with PTC-like nuclear alterations in Hashimoto's thyroiditis. METHODS AND RESULTS: The expression of four genes known to be up-regulated in PTC [LGALS3 (galectin3), CITED1, KRT19 (cytokeratin 19) and FN1 (fibronectin-1)] and the human mesothelial cell protein identified by monoclonal antibody HBME1 was evaluated. Immunohistochemistry was performed on 23 cases of Hashimoto's thyroiditis with focal or diffuse Hürthle cell change and PTC-like nuclear alterations, 37 PTC and 18 normal thyroids. Focal expression of galectin3 (GAL3), CITED1, cytokeratin 19 (CK19), HBME1 and fibronectin-1 (FN1) was seen in 87%, 65%, 43%, 26% and 17% of Hashimoto's thyroiditis, respectively, only in thyrocytes showing PTC-like nuclear alterations. In contrast, diffuse expression of GAL3, CITED1, CK19, HBME1 and FN1 was seen in 100%, 95%, 70%, 87% and 89% of PTC, respectively. Normal thyroid tissues did not express any of these proteins. Following immunohistochemistry, four Hashimoto's thyroiditis cases were found to contain foci of PTC. These foci were highlighted by the diffuse and strong expression of PTC-associated proteins, which prompted additional retrospective scrutiny of the haematoxylin and eosin-stained sections leading to appreciation of complete PTC-type nuclear atypia. CONCLUSIONS: Focal PTC-like immunophenotypic changes in Hashimoto's thyroiditis suggest the possibility of early, focal premalignant transformation in some cases of Hashimoto's thyroiditis.     

Hashimoto's thyroiditis shares features with early papillary thyroid carcinoma

Neoplastic transformation is a multistep process that results in a continuous spectrum from the normal (physiological) state to a fully established neoplasm. The gold standard for diagnosis of papillary thyroid carcinoma is conventional histology, the essential element being the characteristic nuclear features, regardless of whether papillary structures are present or not. However, other criteria are being used increasingly in the diagnosis of neoplasms, including immunohistochemical staining and molecular profile. The RET/PTC gene rearrangement is highly specific for papillary thyroid carcinoma and is associated with the characteristic nuclear features seen in papillary thyroid carcinoma. There is an overlap in the morphological features, immunohistochemical staining pattern, and most importantly, molecular profile between papillary thyroid carcinoma and Hashimoto's thyroiditis. Although considered a 'benign' condition, Hashimoto's thyroiditis almost always harbours a genetic rearrangement that is strongly associated with and is highly specific for papillary thyroid carcinoma. Submicroscopic foci of papillary thyroid carcinoma must be present in Hashimoto's thyroiditis, although the clinical behaviour is still benign. Further studies are required to predict which foci will progress to papillary thyroid carcinoma.     

Malignant T-cell lymphoma of the thyroid gland associated with Hashimoto's thyroiditis

Reported herein is a rare case of malignant T-cell lymphoma of the thyroid gland that developed in a 71-year-old woman with a past history of chronic thyroiditis. The chief complaints were rapidly growing neck mass, weight loss and hoarseness. Presence of abnormal lymphoid cells in the peripheral blood, and an increase in anti-microsome antibodies and anti-thyroglobulin antibodies were found on preoperative laboratory tests. A diagnosis of suspicious malignant lymphoma of the thyroid gland accompanied by Hashimoto's thyroiditis was made, and a total thyroidectomy was performed. Histological examination revealed diffuse small lymphocytic infiltration in the thyroid gland associated with Hashimoto's thyroiditis. Immunohistochemical examination showed that the small lymphocytes were positive for T-cell markers with CD4 predominance. Southern blot analysis of tumor specimens revealed a monoclonal T-cell receptor gene rearrangement. Peripheral T-cell lymphoma was diagnosed. No adjuvant therapy was performed because of the tumor stage and its subtype. The patient is well with no recurrence or metastasis 25 months after the surgical removal of the thyroid. The present case suggests that Hashimoto's thyroiditis might play an important role in the carcinogenesis of thyroid lymphoma not only of B-cell lineage but also of T-cell lineage.     

Immunohistological findings in Hashimoto's thyroiditis,focal lymphocytic thyroiditis and Thyroiditis de Quervain

Summary 65 cases of focal lymphocytic thyroiditis and Hashimoto's disease and five cases of thyroiditis de Quervain were studied with immunohistological methods. In both focal lymphocytic thyroiditis and Hashimoto's disease, lymph follicles with active germinal centers were found which contained germinal center cells that stained positively for intracytoplasmic immunoglobulins (heavy and/or light chains). Positively staining germinal center cells made up only a minor portion of overall immunoglobulin-positive cells; most of the positive infiltrating cells were plasmacytes arranged in small groups or clusters among thyroid follicles. Thus the number of immunoglobulin-containing cells differed greatly between focal lymphocytic thyroiditis, where sites of infiltration were represented by lymph follicles, and Hashimoto's disease. In the former, only a few cells outside lymph follicles stained positively for intracytoplasmic immunoglobulins, whereas in the latter numerous cells within areas of coherent infiltration did. Furthermore, in most cases of Hashimoto's disease macrophages and giant cells with positive staining for lysozyme were present in variable numbers, while in focal thyroiditis they were less frequent or absent. Between these two immunohistologically separable groups, i.e. focal lymphocytic thyroiditis and Hashimoto's disease, there were many cases with features of both. Considering the occurrence of such intermediate forms and some immunohistological similarities between Hashimoto's disease and focal lymphocytic thyroiditis (nearly identical ratio of the different immunoglobulin classes and similar distribution of immunoglobulin-positive germinal center cells), it is likely that these lesions represent different activities of a same immunological process.Thyroiditis de Quervain was characterized immunologically by numerous macrophage clusters and giant cells that both stained positively for lysozyme. Compared with the giant cells seen in Hashimoto's disease (mainly of Langhans type), those of de Quervain's thyroiditis (mainly of foreign body type) were larger and more numerous. Lymph follicles (with or without active germinal centers) were not observed. Among infiltrating cells, numerous plasmacytes that stained positively for intracytoplasmic immunoglobulins were identified. Their number and the distribution pattern of the different classes of immunoglobulins contained within them was similar to those seen in Hashimoto's disease.     

Fine-needle aspiration cytology of papillary Hürthle cell carcinoma with lymphocytic stroma “Warthin-like tumor” of the thyroid

Papillary Hürthle cell carcinoma with lymphocytic stroma is a recent addition to the list of variants of papillary carcinoma of the thyroid. We report the aspiration cytology and histology findings of this tumor arising in two patients. The smears were cellular, and revealed Hürthle cells arranged in three-dimensional groups, papillary fragments, and as singly dispersed cells with a prominent intimately associated inflammatory component of lymphocytes and few plasma cells. The Hürthle cells were pleomorphic and showed granular eosinophilic cytoplasm, eccentrically oriented nuclei with prominent nucleoli. Nuclear features of papillary carcinoma were present among both the cellular groups and scattered cells. The histologic examination showed a circumscribed papillary tumor comprising Hürthle cells and a brisk inflammatory component filling the stalks of papillae. These findings were consistent with a papillary Hürthle cells carcinoma with lymphocytic stroma, the so-called Warthin-like tumor of the thyroid. Hürthle cells admixed with inflammatory cells in cytology preparations can be seen in Hürthle cell nodules or neoplasms arising in a background of chronic lymphocytic thyroiditis. We suggest that a careful search for nuclear features may be helpful in diagnosing this variant of papillary carcinoma.     

Hemangioma of the thyroid gland in an adolescent with chronic lymphocytic thyroiditis and adenomatous hyperplasia

We report a case of benign hemangioma of the thyroid gland which involved one lobe of the thyroid gland in an adolescent female with classic chronic lymphocytic thyroiditis and adenomatous hyperplasia. The lesion produced a clinical picture suspicious for malignancy owing to the presence of a very large cold nodule on scan, lack of response to TSH suppression, and the subsequent development of an enlarged cervical lymph node. The histologic and immunohistologic findings, including positive staining for factor VIII-related antigen,Ulex europaeous lectin, CD31, CD34, and the presence of linear staining for type IV collagen and laminin are consistent with a hemangioma. In our review of the literature, only one other report of a hemangioma of the thyroid gland was found.     

Diagnostic problems in thyroid FNAs

The use of FNA cytology to diagnose pathologic conditions of the thyroid has increased considerably in recent years, particularly since it has reduced by half the number of patients undergoing surgery. On the one hand, this diagnostic technique has attracted a certain amount of well justified criticism, but on the other, recent cytohistologic correlations and new scientific knowledge are continually improving its application. We shall discuss the latter aspect in more detail and deal with some simple but informative points which the pathologist may find useful in daily practice. Diagn. Cytopathol. 1997;17:422–428. © 1997 Wiley-Liss, Inc.     

甲状腺乳头状癌合并桥本氏甲状腺炎右侧喉返神经深层淋巴结转移情况分析

目的:探讨甲状腺乳头状癌(PTC)合并桥本氏甲状腺炎(HT)患者右侧喉返神经深层淋巴结(LN-prRLN)的转移情况.方法:选取本院2015年7月至2019年12月收治的123例PTC合并HT及150例单纯PTC病例为研究对象,分为观察组、对照组.所有患者均行中央区淋巴结完整清扫,比较2组颈部中央区淋巴结转移情况,分析...     

B-RAF mutations in the etiopathogenesis, diagnosis, and prognosis of thyroid carcinomas

The very recent discovery of B-RAF point mutations as the most prevalent genetic alteration in papillary thyroid carcinoma has revolutionized the molecular knowledge of thyroid malignancies. In this review, we address the role played by such mutations in the etiopathogenesis, diagnosis, prognosis, and therapy selection of thyroid cancer, with an emphasis on papillary carcinoma.     

Three-dimensional reconstruction of vessel distribution in benign and malignant lesions of thyroid

In order to better understand the spatial distribution of thyroid vessels, a series of benign and malignant thyroid lesions were studied with three-dimensional (3D) histological stereomicroscopic reconstruction. Cases consisted of normal autoptic thyroids (n=6), colloid goitres (n=6), Basedows disease (n=2), follicular adenoma (FA) (n=4) one of which with Hurthle cells (HC), minimally invasive, well-differentiated follicular carcinoma (FTC) (n=1), well-differentiated FTC with HC (n=1), poorly differentiated FTC (n=13) with extensive angioinvasion, papillary carcinoma (PTC) (n=8) and medullary carcinoma (MTC) (n=1). From each selected nodule, parallel sections were obtained for 3D reconstruction and for histological and immunohistochemical studies. In normal thyroid, large vessels were located at the periphery of the gland with smaller branches present within the thyroid parenchyma that encircled follicles. The same pattern of vascularisation is maintained in lesions showing a follicular architecture as colloid goitre, Basedows disease, FA, well-differentiated FTC and the follicular variant of PTC. Neoplastic lesions, at variance with non-neoplastic lesions, contained rare anastomoses. Poorly differentiated FTC and MTC contained large intratumoural vessels surrounding avascular areas corresponding to solid neoplastic cellular sheets with necrosis. PTC were more vascularised and contained numerous vascular anastomoses. In conclusion, the present data indicate that the vascular distribution is related to the follicular, papillary or solid type of growth. Vascular anastomoses and intratumoural vessels surrounding solid avascular areas are signs of malignancy.     

Incidence of neoplasia in Hashimoto's thyroiditis: A fine-needle aspiration study

There is a recognized association between Hashimoto's thyroiditis (HT) and thyroid neoplasms. We reviewed fine-needle aspirations (FNAs) from 90 patients with HT to assess the contribution of this procedure. For seven patients, FNA showed HT and follicular neoplasm (n = 6) or HT and papillary carcinoma (n = 1). Eighteen patients underwent thyroid resection. Three patients had follicular adenomas which were not detected by FNA, one patient had papillary carcinoma confirmed, and six patients with follicular neoplasm by FNA were negative for tumor. Thus, 4% of our patients had confirmed neoplasms, an incidence lower than usually reported. One reason for the lower rate of neoplasia in our series was misinterpretation of follicular neoplasia in the background of HT. The cytologic changes in the hyperplastic follicular and metaplastic oncocytic epithelium are similar to those seen in follicular neoplasm. Our study suggests that these processes may be indistinguishable, and thus, in the presence of HT, the diagnosis of follicular neoplasm probably should not be rendered. Diagn Cytopathol 1996;14:38–42. © 1996 Wiley-Liss, Inc.     

桥本甲状腺炎伴不典型细胞与乳头状癌的鉴别诊断

目的：探讨桥本甲状腺炎伴不典型细胞与甲状腺乳头状癌( papillary thyroid carcinoma,PTC)的鉴别诊断。方法收集桥本甲状腺炎153例,分为桥本甲状腺炎伴不典型细胞组(32例)、桥本甲状腺炎伴PTC组(49例)、桥本甲状腺炎对照组(72例)。采用HE及免疫组化法分析各组间的差异。结果桥本甲状腺炎伴不典型细胞与PTC有形态学差异。伴PTC组Galec-tin-3、CK19阳性率高于伴不典型细胞组,CD56阳性率低于伴不典型细胞组,差异均有统计学意义。 Ki-67阳性率在伴不典型细胞组与伴PTC组之间差异无显著性,但与对照组之间差异有统计学意义。结论以组织形态学特征为基础,联合应用CD56、CK19、Galectin-3、Ki-67可有效鉴别桥本甲状腺炎伴不典型细胞与PTC。     

Follicular thyroid lesions coexisting with Hashimoto's thyroiditis: incidence and possible sources of diagnostic errors

Our objectives were to study the types and incidence of thyroid follicular lesions coexisting with Hashimoto's thyroiditis (HT), the pitfalls in their cytodiagnosis, and the effect on management. All cases of HT diagnosed by fine-needle aspiration (FNA) and/or histology over a 7-yr period were retrospectively studied. HT coexisted with follicular adenoma (FA) in 6 cases, follicular variant of papillary carcinoma (FVPC) in 1 case, and goitrous nodule (GN) in 2 cases. The overall incidence rates of thyroid neoplasm and goitrous nodules coexistent with HT were 15% and 3.5%, respectively. A preoperative FNA diagnosis was available in 10 histologically proven cases of HT. A false-positive diagnosis of follicular neoplasm (FN) that led to unnecessary thyroidectomies was given in 3 cases. In 2 of these, the cytological diagnosis was HT with the possibility of coexisting FN, and in the third case, the cytological finding of HT was misinterpreted as FN. The main causes of these diagnostic pitfalls were the presence of hyperplastic follicular cells with nuclear pleomorphism, a paucity of lymphoid cells in burned-out HT, and lack of ones exposure. Nuclear pleomorphism was observed in none of the follicular adenomas. FNA diagnosed accurately the coexisting lesions in 6 cases; 3 FA, 1 FVPC, and 2 GN, but it did not sample HT. In one case, FNA diagnosed correctly both HT and the coexisting FA. Therefore, the presence of a coexistent neoplasm or goitrous nodule reduced the chances of sampling HT by 85.7%, with no false-negative results. Indeed, aspiration on and around the thyroid nodule helps in sampling HT. However, HT may dominate the smear and obscure neoplasia. This can be avoided if the procedure is performed by the pathologist and the aspiration is done on the nodule only. The overlapping cytological features of FN and HT were the main causes of false-positive results. This can be reduced by avoiding the diagnosis of FN in the presence of follicular-cell pleomorphism and/or moderate to excessive numbers of lymphoid cells, provided proper aspiration technique is maintained.     

The p75 neurotrophin receptor is widely expressed in conventional papillary thyroid carcinoma

Papillary thyroid carcinomas (PTCs) are associated with alterations in several proto-oncogenes related with nervous system development and function, such as TrkA and RET, which are commonly rearranged in these carcinomas. The other oncogenic event recently identified in PTC is the BRAF V600E mutation. Because the role of TrkA was not completely elucidated in thyroid cancer ethiopathogenesis, we decided to study the expression of active, phosphorylated TrkA and of its coreceptor p75 neurotrophin receptor (p75 NTR) in a series of 92 PTC (37 lesions of conventional PTC, 28 of follicular variant of PTC [FVPTC], and 27 of other variants of PTC) as well as in 21 samples of normal thyroid and nonneoplastic thyroid lesions used as a controls. We observed neoexpression of p75 NTR in PTC, particularly in conventional PTC and in other variants of PTC displaying a papillary growth pattern, rather than in FVPTC. No immunoexpression of p75 NTR was observed in normal thyroid nor in nonneoplastic thyroid lesions. The cellular localization of p75 NTR immunoexpression was also significantly associated with the growth pattern of PTC, being much more frequently detected in an apical localization in PTC with papillary architecture than in PTC with a follicular or solid growth pattern. This apical localization of p75 NTR was significantly associated with the presence of BRAF V600E. No significant differences were detected between normal thyroid, nonneoplastic lesions, and PTC (or any PTC variant) regarding expression/activation of TrkA, thus suggesting that by itself and in contrast to p75 NTR, TrkA is not altered during PTC development.