Distinct histopathological features of Hashimoto's thyroiditis with respect to IgG4-related disease

A form of Hashimoto's thyroiditis with lymphoplasmacytic sclerosing changes and increased numbers of IgG4-positive plasma cells has recently been reported in the literature. These histopathological features suggest that this subtype of Hashimoto's thyroiditis may be closely related to IgG4-related disease. Therefore, this unique form of IgG4-related Hashimoto's thyroiditis, which is referred to as IgG4 thyroiditis, has its own clinical, serological, and sonographic features that are distinct from those associated with non-IgG4 thyroiditis. IgG4 thyroiditis shares similarities with the well-known fibrous variant of Hashimoto's thyroiditis; however, the detailed histopathological features of IgG4 thyroiditis have not been well established. Based on immunostaining results, 105 patients with Hashimoto's thyroiditis were divided into an IgG4 thyroiditis group (n=28) and a non-IgG4 thyroiditis group (n=77). As in our previous reports, IgG4 thyroiditis was associated with a patient population of a younger age, a lower female-to-male ratio, rapid progression, higher levels of thyroid autoantibodies, subclinical hypothyroidism, and diffuse sonographic echogenicity. Histopathologically, this group revealed severe lymphoplasmacytic infiltration, dense stromal fibrosis, marked follicular cell degeneration, numerous micro-follicles, and notable giant cell/histiocyte infiltration. Importantly, the IgG4-related group did not completely overlap with fibrous variant of Hashimoto's thyroiditis. Four cases (14%) in the IgG4 thyroiditis group presented only mild fibrosis in the stroma, whereas 29 cases (38%) in the non-IgG4 thyroiditis group met the diagnostic criteria for fibrous variant of Hashimoto's thyroiditis. Furthermore, we observed three patterns of stromal fibrosis in Hashimoto's thyroiditis: interfollicular fibrosis, interlobular fibrosis, and scar fibrosis. The IgG4 thyroiditis group was significantly associated with the presence of predominant interfollicular fibrosis. In conclusion, IgG4 Hashimoto's thyroiditis presents histopathological features quite distinct from its non-IgG4 counterpart.     

Thyroid blocking antibodies in thyroiditis

Serum from a woman with a history of Hashimoto's thyroiditis, who had given birth to two children with congenital hypothyroidism, contained potent TSH blocking activity. Immunoglobulin preparation from this serum abolished completely TSH-stimulated cAMP production in human thyroid membranes. The blocking activity was associated with the IgG fraction absorbed to and eluted from a Protein A column. The stimulation of adenylate cyclase by a preparation of thyroid-stimulating antibodies from a patient with Graves' disease was also inhibited by the antibodies. In contrast, no effect was observed upon fluoride-stimulated cAMP production. The data indicate that the antibody activity was directed against the TSH receptor. Immunoglobulin preparations from 22 other patients with Hashimoto's thyroiditis and 16 patients with subacute thyroiditis were examined for the existence of TSH receptor blocking antibodies. A blocking activity was found in two of the 22 Hashimoto patients. No such activity was found in the patients with subacute thyroiditis. It appears that thyroid blocking antibodies sometimes contribute to hypothyroidism associated with Hashimoto's thyroiditis.     

A 20-year-old woman with Hashimoto's thyroiditis and Evans' syndrome

Here we report the case of a 20-year-old female patient previously diagnosed with Hashimoto's thyroiditis and overt hypothyroidism, and who had been taking synthetic thyroxine (100 microg/day) for eight months. She experienced intermittent dizziness and generalized weakness, and was diagnosed as having severe autoimmune hemolytic anemia (AIHA). We prescribed prednisolone treatment and continued synthetic thyroxine administration. Two years and five months later, she developed idiopathic thrombocytopenic purpura (ITP) and was diagnosed with Evans' syndrome. Thereafter, laparoscopic splenectomy was performed because her autoimmune hemolytic anemia was refractory and dependent on steroid therapy. The HLA genotypes of the patient were HLA-A*020101/A* 2602, HLA-B*270502/B*5401, HLA-Cw*0102/Cw*020202, HLA-DRB1*0404/DRB1*0405, and HLA-DQB1*0302/DQ B1*0401. Hashimoto's thyroiditis is often associated with other nonendocrine autoimmune diseases, and antithyroid antibodies are frequently observed in Evans' syndrome (coexistence of AIHA and ITP). However, there is no report of Evans' syndrome developing in patients with overt hypothyroidism and Hashimoto's thyroiditis. This case suggests that three autoimmune diseases (AIHA, ITP, and Hashimoto's thyroiditis) might share a common immunogenetic pathway in pathogenesis.     

Investigation of the clonality of lymphocytes in Hashimoto's thyroiditis using immunoglobulin and T-cell receptor gene probes

Southern blotting and DNA hybridization were used for the detection of immunoglobulin and T-cell receptor gene rearrangements in thyroid tissue from six patients with Hashimoto's thyroiditis, three patients with B-cell lymphoma complicating Hashimoto's thyroiditis, and two patients with nonspecific lymphocytic thyroiditis. Immunoglobulin gene rearrangements were detected only in patients with histologic evidence of lymphoma. A single T-cell receptor beta-chain gene rearrangement was detected in one of the patients with uncomplicated Hashimoto's thyroiditis. Based on our knowledge of primary thyroid lymphomas, it is highly unlikely that this case represents an early, histologically occult T-cell lymphoma. The uniform lack of immunoglobulin gene rearrangements in Hashimoto's thyroiditis supports the use of genotypic analysis in differentiating between uncomplicated Hashimoto's thyroiditis and non-Hodgkin's lymphoma. The finding of a T-cell receptor gene rearrangement in a case of Hashimoto's thyroiditis suggests that the immune response in this disease occasionally may be clonally restricted.     

HL-A antigens in Graves' disease and Hashimoto's thyroiditis.

An increased frequency of HL-A 1 and HL-A 8 was found in patients with Graves' disease and Hashimoto's thyroiditis, whem compared to a control group from the same geographic area, and drawn from a pool of subjects attending one diagnostic centre. Furthermore, an increased incidence of W15 and W17 was found in Hashimoto's thyroiditis; however, these were not detected in any patient with Graves' disease.     

Hashimoto's thyroiditis and membranous nephropathy developed in progressive systemic sclerosis (PSS)

A case of a 36-year-old woman with progressive systemic sclerosis (PSS) was reported. The patient had two additional immune-mediated diseases: Hashimoto's thyroiditis and membranous nephropathy. It was implicated that overlapping of systemic lupus erythematosus (SLE) occurred in the course of PSS. Notably, immune complex deposition along the follicular basement lamina of the thyroid was suggested by immunofluorescence and electron microscopy. Although the glomerular lesion was in general accord with membranous nephropathy, it was complicated by occasional crescent formations and necrotic arterial changes, probably resulting from malignant hypertension that appeared during the terminal stage. It was implied that the same circulating antigen-antibody complexes might have been involved in the pathogenesis of Hashimoto's thyroiditis and membranous nephropathy in this case.     

A thyroid biopsy with histologic features of both Riedel's thyroiditis and the fibrosing variant of Hashimoto's thyroiditis.

We describe a 36-year-old woman with clinical, laboratory, and histologic features of both Riedel's thyroiditis and the fibrosing variant of Hashimoto's thyroiditis. Features of the former included a hard, fixed thyroid mass and extensive involvement of perithyroidal tissues by dense fibrosis with lymphocytes, histiocytes, and plasma cells. Features supporting Hashimoto's thyroiditis included high serum titers of antimicrosomal and antithyroglobulin antibodies and the histologic findings within the thyroid gland itself: dense fibrous bands dividing the thyroid parenchyma into nodules composed of lymphoid follicles with germinal centers, plasma cells, and oxyphilic metaplasia of follicular epithelial cells. Although Riedel's thyroiditis and the fibrosing variant of Hashimoto's thyroiditis were once considered morphologic variants of the same disease, since the 1970s these diseases have been considered as distinct clinicopathologic entities. The coexistence of both diseases in a patient is rare and is probably coincidental in this instance.     

Fine-needle aspiration of Riedel's disease: report of a case and review of the literature

The cytomorphological features of a case of Riedel's thyroiditis (Riedel's disease) in a 37-yr-old woman are reviewed. The patient presented with a diffusely enlarged thyroid gland with extension to carotid and jugular vessels bilaterally. A fine-needle aspiration of the right lobe of the thyroid demonstrated moderate cellularity with fragments of fibrous tissue with bland spindle-shaped cells and myofibroblasts. The patient subsequently underwent a bilateral subtotal thyroidectomy with removal of two-thirds of both lobes of the thyroid. A frozen section diagnosis of Riedel's disease was later confirmed on paraffin sections. Here we describe the cytological findings of a case of Riedel's disease and provide some helpful clues in distinguishing it from other forms of thyroiditis such as fibrosing variant of Hashimoto's thyroiditis, subacute thyroiditis, or granulomatous thyroiditis and from malignancy with which it can be confused both clinically and cytologically.     

A differential association of interferon-gamma high-producing allele T and low-producing allele A (+874 A/T) with Hashimoto's thyroiditis and Graves' disease

Cytokines play a crucial role in the pathogenesis of autoimmune thyroid disease. The aim of this study was to investigate the relationship of the single base change polymorphic variants identified in the first intron of interferon-gamma (IFN-gamma) (+874 T/A) with susceptibility to thyroid dysfunctions. A total of 340 subjects were included in the study comprising of 190 patients (104 patients with Hashimoto's thyroiditis, 26 with non-Hashimoto's hypothyroidism and 60 Graves' disease) and 150 controls. Genotyping was done by amplification refractory mutation system-polymerase chain reaction using a set of sequence-specific primers. Statistical analysis revealed a significant association between high IFN-gamma-producing genotype TT and Hashimoto's thyroiditis compared to controls (P value < 0.001). On the other hand, the frequency of genotype TT was decreased in patients with Graves' hyperthyroidism with a significant increase in low IFN-gamma-producing genotype AA among this group (P = 0.03). To conclude the results of the study suggest a differential association of high- and low-producing alleles of IFN-gamma gene with Hashimoto's thyroiditis and Graves' disease. The high IFN-gamma-producing allele T was observed to be associated with Hashimoto's thyroiditis in the present study where as in Graves' hyperthyroidism the association was observed to be stronger with the low producing allele A.     

Hashimoto's disease in a bilateral benign cystic ovarian teratoma: a case report

A wide array of tissues derived from all the three germinal layers is seen in ovarian teratomas. Among these, thyroid tissue is present in 10% cases of all mature cystic teratomas. We report this case of Hashimoto's thyroiditis in a clinically euthyroid patient who tested positive for antithyroid peroxidase antibodies in spite of normal thyroid hormone profile. While the histological features of several disorders of thyroid tissue may be discovered, Hashimoto's thyroiditis is extremely rare finding in ovarian teratomas.     

Fas ligand gene polymorphisms are not associated with Hashimoto's thyroiditis and Graves' disease

Hashimoto's thyroiditis and Graves' disease represent the two most common autoimmune thyroid disorders. Whereas in Hashimoto's thyroiditis FasL expression causes thyrocytes to undergo apoptosis, additional anti-apoptotic molecules appear to protect these cells in Graves' disease. Mutations of the FasL gene were observed in systemic lupus erythematosus. Given its functional relevance for the pathogenesis of thyroid autoimmunity we wondered whether variants of the FasL gene play a role in Hashimoto's thyroiditis and Graves' disease. We genotyped families with at least one offspring affected by Hashimoto's thyroiditis (n = 86) and Graves' disease (n = 90) for two FasL gene polymorphisms (C -843 T in the promoter, A IVS2nt-124 G in intron 2). Extended transmission disequilibrium (ETDT) and chi(2) testing were performed. Neither polymorphism alone nor the promoter/intron 2 haplotypes (p = 0.91) were associated with Hashimoto's thyroiditis. No association with Graves' disease was observed for the promoter polymorphism (p = 0.91) and the intron 2 "A" allele (57.1%; p = 0.36) or the promoter/intron 2 haplotypes (p = 0.31). Moreover, intron 2 genotyping revealed no difference between an additional 251 patients with Graves' disease and 197 healthy controls (p = 0.37). Italian and German families did not differ for the studied polymorphisms. In conclusion, our data do not suggest common genetic FasL variants to significantly contribute to the pathogenesis of either Hashimoto's thyroiditis or Graves' disease.     

Lymphocytic thyroiditis in fine-needle aspirates: differential diagnostic aspects

This study assessed the morphological criteria for the diagnosis of various types of lymphocytic thyroiditis in fine-needle aspirates. Of 950 aspirates, 121 revealed lymphocytic thyroiditis, including Hashimoto's thyroiditis (partly confirmed by serological or histological examination) and focal thyroiditis adjacent to neoplasms. The diagnosis of Hashimoto's thyroiditis was easy when the aspirated material was adequate and contained oxyphilic cells; in the fibrous type, diagnosis was rather difficult. Focal thyroiditis may be confused with Hashimoto's thyroiditis, especially when adjacent to neoplasm. Surgical exploration should be performed in cases of severe lymphocytic thyroiditis revealed by fine-needle aspiration with repeatedly negative antibody titers in order to exclude neoplasm.     

HTLV-I infection in patients with autoimmune thyroiditis (Hashimoto's thyroiditis).

To investigate the possible relationship of HTLV-I virus infection to autoimmune thyroid disease, we examined, firstly, the frequency of HTLV-I seropositivity among patients with Hashimoto's thyroiditis and, secondly, the frequency of Hashimoto's thyroiditis in patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). Of 144 patients with Hashimoto's thyroiditis in the Tokushima and Kochi Prefectures, Japan, 9 (6.3%) were positive for serum HTLV-I virus antibody 2 of whom were confirmed histologically to have Hashimoto's thyroiditis. This percentage is significantly higher (P < 0.01) than the estimated prevalence (2.2%) of HTLV-I carriers among the general population in this region. Of 9 patients with HAM/TSP, 3 (33.3%), including 2 biopsy-proven cases, had evidence of Hashimoto's thyroiditis. This proportion is apparently much higher than the prevalence (1.7%) of Hashimoto's thyroiditis in the general population. These findings suggest that HTLV-I virus may be related to the development of Hashimoto's thyroiditis.     

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.     

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.     

Immunohistochemistry of IgG4 can help subclassify Hashimoto's autoimmune thyroiditis

IgG4-related sclerosing disease has been recently recognized as a systemic disease entity characterized by an elevated serum IgG4 level, sclerosing fibrosis and diffuse lymphoplasmacytic infiltration by many IgG4-positive plasma cells. Similar histopathological features have often been noted in the fibrous variant of Hashimoto's autoimmune thyroiditis, but thyroid gland involvement has been only briefly mentioned with regard to IgG4, and no immunohistochemistry for IgG4 has been reported in Hashimoto's autoimmune thyroiditis. Herein, the purpose of the present study was to investigate the infiltration of IgG- and IgG4-positive plasma cells on immunohistochemistry for a panel of thyroiditis samples (Hashimoto's autoimmune thyroiditis, n = 13; subacute thyroiditis, n = 2; lymphocytic thyroiditis, n = 2). Cases of Hashimoto's thyroiditis could be classified into two groups based on immunostaining of IgG4: IgG4 thyroiditis (IgG4-related, IgG4-positive plasma cell-rich thyroiditis) and non-IgG4 thyroiditis (non-IgG4-related, IgG4-positive plasma cell-poor thyroiditis). IgG4 thyroiditis presents with severe lymphoplasmacytic infiltration, dense fibrosis, marked follicular cell degeneration, oxyphilic change and lymphoid follicle formation, while non-IgG4 thyroiditis presents with relatively mild or absent histopathological characteristics. In conclusion, immunostaining of IgG4 can help subclassify Hashimoto's thyroiditis; and IgG4 thyroiditis may have a close relationship with IgG4-related sclerosing disease.     

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.     

Gonadal dysgenesis with Graves''s disease.

Hashimoto's thyroiditis has previously been associated with gonadal dysgenesis. Recent evidence suggests that Graves's disease and Hashimoto's thyroiditis are disorders of cell-mediated immunity and may have a common genetic predisposition. However, patients with both Graves's disease and the Turner syndrome have been reported only rarely. Three such cases are presented and the relation among gonadal dysgenesis, Hashimoto's thyroiditis, and Graves's disease is discussed.     

Post-partum thyroiditis and goitrous (Hashimoto's) thyroiditis are associated with HLA-DR4

Using new panels of HLA-DR typing sera, we found an increase in the prevalence of HLA-DR4 in 21 patients with Hashimoto's thyroiditis (57%) and 32 patients with post-partum thyroiditis (53%) compared to controls (21%). Hashimoto's thyroiditis was previously found to be associated with HLA-DR5 and Dw5. We feel that the doubts raised by this study warrant the study of DR antigens in thyroid autoimmune disease using large panels of specific sera.     

Fibrous thyroiditis—an immunopathological study

Riedel's thyroiditis is a rare disease which has in the past been confused with the much commoner fibrous variant of Hashimoto's thyroiditis. We have compared the histological and immunohistochemical characteristics of three cases diagnosed as Riedel's thyroiditis with five cases of the fibrous variant of Hashimoto's thyroiditis. The major distinguishing features on light microscopic study were that Riedel's thyroiditis showed (a) extra-thyroid extension of the fibrous tissue, (b) a phlebitis with distension of the vein lumen by lymphoid or fibrous tissue, and (c) relatively normal surviving thyroid tissue, while in Hashimoto's thyroiditis the fibrous tissue did not extend outside the thyroid, the veins were surrounded by fibrous tissue, but did not show a phlebitis, and all thyroid tissue was affected by the process. These findings confirm those of other workers in suggesting that there is a clear histological distinction between these two processes. The quantitative immunohistochemical studies showed that in the fibrous variant of Hashimoto's thyroiditis, cells containing kappa chains outnumbered lambda chain cells in all cases, the mean ratio of kappa to lambda being very close to that found generally in the circulation, with lambda chain cells forming 36% of all light chain containing cells. In contrast, the mean proportion of lambda chain cells in Riedel's thyroiditis was 71%. In Hashimoto's thyroiditis the dominant plasma cell was, as expected, the IgG containing cell, with IgA cells forming only 15% of all heavy chain cells. In Riedel's thyroiditis IgA containing plasma cells were unusually prominent, forming 47% of all plasma cells present. These findings confirm the separation of the two entities, and demonstrate an unusual pattern of restriction of antibody forming cells in Riedel's thyroiditis. It is possible that IgA plays a role in the pathogenesis of Riedel's thyroiditis.