Emiko Taniguchi

Distinct Clinical, Serological, and Sonographic Characteristics of Hashimoto’s Thyroiditis Based with and without IgG4-Positive Plasma Cells

CONTEXT IgG4-related sclerosing disease is a new syndrome characterized by high serum IgG4 levels and increased IgG4-positive plasma cells in the involved organs. Recently the first description was made by our group of a subsection of Hashimotos autoimmune thyroiditis (HT) patients showing indistinguishable histopathological features with IgG4-related sclerosing disease, which was termed as IgG4 thyroiditis. OBJECTIVE The objective of the study was analysis of the immunophenotypic features of IgG4 in 70 cases of HT patients and to clarify the histopathological and clinical characteristics of the patients with IgG4 thyroiditis. DESIGN Thyroid tissue samples were obtained from 70 patients with HT who were treated surgically. Quantitative analyses of the expression of IgG4 and IgG were performed. Statistical analyses of clinical and histopathological parameters were also conducted. RESULTS On the basis of immunohistochemistry of IgG4 and IgG4/IgG ratio, the 70 patients with HT were divided into two groups: IgG4 thyroiditis (19 cases) and non-IgG4 thyroiditis (51 cases). Histopathologically, IgG4 thyroiditis showed higher grade of stromal fibrosis, lymphoplasmacytic infiltration, and follicular cell degeneration than non-IgG4 thyroiditis. Moreover, these two groups were also demonstrated to be related with different clinical features, with IgG4 thyroiditis associated more with male gender, rapid progress, subclinical hypothyroidism, more diffuse low echogenicity, and higher level of circulating antibodies. CONCLUSIONS From both clinical and histopathological aspects, IgG4 thyroiditis and non-IgG4 thyroiditis were demonstrated to be distinct entities. Measuring serum IgG4 concentration provides a useful method of distinguishing IgG4 thyroiditis from non-IgG4 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 Hashimotos autoimmune thyroiditis, but thyroid gland involvement has been only briefly mentioned with regard to IgG4, and no immunohistochemistry for IgG4 has been reported in Hashimotos 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 (Hashimotos autoimmune thyroiditis, n= 13; subacute thyroiditis, n= 2; lymphocytic thyroiditis, n= 2). Cases of Hashimotos 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 Hashimotos thyroiditis; and IgG4 thyroiditis may have a close relationship with IgG4‐related sclerosing disease.

Encapsulated follicular thyroid tumor with equivocal nuclear changes, so-called well-differentiated tumor of uncertain malignant potential: a morphological, immunohistochemical, and molecular appraisal

There is a continuous debate regarding the classification of thyroid follicular lesions and the term “well‐differentiated tumor of uncertain malignant potential (WDT‐UMP)” was recently introduced to cover this problematic spectrum of tumors. The objective of this study was to reappraise WDT‐UMP using morphological, immunochemical, and molecular analysis and to shed more light on encapsulated thyroid follicular‐patterned tumors. A total of 30 cases of WDT‐UMP with equivocal papillary thyroid carcinoma‐type nuclear changes (PTC‐N) or focal unequivocal PTC‐N were examined. As a control, follicular adenoma (n = 29), follicular carcinoma (n = 8), hyalinizing trabecular adenoma (n = 5), and PTC (n = 48) were included. HBME‐1, cytokeratin 19, and galectin‐3 were positive in 12 (40.0%), 10 (33.3%) and 11 (36.7%) cases of WDT‐UMP, respectively. According to the positivity of those markers, significant differences were obtained between WDT‐UMP and PTC encapsulated common type (P = 0.028, 0.010, and 0.004, respectively), infiltrative follicular variant (P = 0.020, 0.026, and 0.008, respectively), and infiltrative common type (P = 0.004, 0.001, and 0.005, respectively), but not between WDT‐UMP and follicular adenoma or follicular carcinoma. BRAFV600E mutation was absent but RET/PTC1 rearrangement was found in only two (6.7%) cases of WDT‐UMP. None of the 20 patients with WDT‐UMP developed recurrence, with an average follow‐up of 80 months. These findings indicate that WDT‐UMP has a favorable outcome and is distinct from PTC in morphological, immunohistochemical, and molecular characteristics. We propose that WDT‐UMP should be classified as “well‐differentiated tumor with uncertain behavior”. (Cancer Sci 2011; 102: 288–294)

Survival impact of psammoma body, stromal calcification and bone formation in papillary thyroid carcinoma

The presence of calcification is the most significant ultrasonographic finding in evaluating thyroid nodules. Calcifications are more frequently detected in papillary thyroid carcinoma than in other thyroid lesions. However, the clinical significance of calcification, including clinical correlations and impact on survival, and the molecular mechanism responsible for calcification in papillary thyroid carcinoma remain uncertain. We performed a retrospective study of patients with primary common-type papillary thyroid carcinoma to determine the clinical correlations of calcification and its impact on survival. Histologically, calcification was classified as either psammoma bodies, stromal calcification, or bone formation. They were identified in 25, 47, and 13% of all 229 cases of papillary thyroid carcinoma, respectively. The presence of psammoma bodies was significantly correlated with gross lymph node metastasis and stage grouping. Both stromal calcification and bone formation were significantly correlated with patient age. In addition, stromal calcification was associated with pT classification and gross lymph node metastasis. Papillary thyroid carcinoma with, compared to that without, psammoma bodies was associated with poorer disease-free survival. We examined the quantitative expression of BMP-1, a metalloproteinase that is reported to be involved in bone and extracellular matrix formations, and found that its expression was significantly higher in tumors with psammoma bodies or with stromal calcification (P=0.0464 and 0.0272, respectively). These results suggest that the presence of psammoma bodies is a useful predictor of outcome for patients suffering from papillary thyroid carcinoma.

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.

Loss of cellular polarity/cohesiveness in the invasive front of papillary thyroid carcinoma, a novel predictor for lymph node metastasis; possible morphological indicator of epithelial mesenchymal transition

Background Loss of cellular polarity/cohesiveness (LOP/C) in the invasive front of papillary thyroid carcinoma (PTC) results in a high recurrence risk of PTC. Aims To investigate the immunohistochemical features of LOP/C in PTC and to show that this feature is linked to a high association of lymph node metastasis (LNM) at surgery and tumour recurrence. Methods The degree of LOP/C of the PTCs was evaluated histologically using a cut-off value of 20% and the immunohistochemical features of LOP/C were analysed using immunohistochemical staining for E-cadherin, β-catenin and vimentin. The relationship between the LOP/C and the other clinicopathological parameters was analysed. Results 43 cases of PTC with LOP/C (≥20%) were selected and 27 cases with LOP/C (<20%) were included as control tumours. 11/44 cases (25%) were observed to develop recurrence, LNM or distant metastasis at an average follow-up of 31 months. Less expression of E-cadherin and aberrant localisation of β-catenin and vimentin were observed in PTC tumour cells with LOP/C. LOP/C (≥20%) was significantly correlated with extrathyroid invasion (r=0.336, p=0.003), advanced tumour stage (r=0.275, p=0.017), LNM (r=0.389, p<0.001) and recurrence after surgery (r=0.302, p=0.036). Both extrathyroid invasion and LOP/C were independent significant predictors of LNM. Conclusions LOP/C may be a useful morphological feature of epithelial mesenchymal transition under H&E observation, and it is an important indicator of lymph node metastasis and aggressive clinical behaviour of PTC.

Cytologic grading of invasive breast carcinoma : Correlation with clinicopathologic variables and predictive value of nodal metastasis

OBJECTIVE To estimate cytologic grade and correlate it with the other known prognostic factors, such as tumor differentiation, growth fraction, estrogen receptor status and nodal status. STUDY DESIGN Fine needle aspirates from 104 invasive ductal carcinomas were stained by the Papanicolaou method and examined for necrosis, cellular size, nuclear/cytoplasmic ratio, nuclear pleomorphism, nucleoli, chromatin granularity and density of chromatin. We established a semiquantitative scoring system based on the above features and correlated cytologic findings with clinicopathologic variables. RESULTS Histologic grade correlated positively with cytologic grade and negatively with estrogen receptor positivity. Moreover, high cytologic grade was associated with nodal metastasis and proliferative index labeling by MIB-1. CONCLUSION This study showed that our grading system for breast cancer on fine needle aspiration cytology is feasible on a routine diagnostic basis. Cytologic grading can provide more information than usual on tumor biologic behavior.

Correlation between nuclear grade and biological prognostic variables in invasive Breast Cancer

BackgroundGrading of carcinomas is an estimation of differentiation. Nuclear grading is the cytological evaluation of tumor nuclei in comparison with the nuclei of normal mammary epithelial cells. Because nuclear grading does not involve an assessment of the growth pattern of the tumor, it applies not only to invasive ductal carcinoma but also to other subtypes of breast carcinoma.MethodsA total of 215 primary breast carcinomas obtained from the Affiliated Kihoku Hospital of Wakayama Medical College were enrolled in our present study. Nuclear grade was evaluated according to the criteria of the National Surgical Adjuvant Study of Breast Cancer (NSAS-B) protocol. Immuno-histochemistry was also performed to determine Bcl-2, p53, c-erbB-2, estrogen receptor (ER) and MIB-1 expression in paraffin-embedded tissues for all cases.ResultsThirty-two (14.9%) of the patients were graded as 1,124 (57.7%) as 2, and 59 (27.4%) as 3. Nuclear grade displayed a negative correlation with Bcl-2 expression (r=0.308, p<0.0001), and a positive correlation with c-erbB-2 overexpression (r= 0.172, p=0.01 17) and tumor proliferative index labeling by MIB-1 (r=0.485, p<0.0001).ConclusionsThese results imply that nuclear grade is related to the characteristics of tumor biology, indicating that the morphology and biology of breast cancer are tightly linked. Our present results also suggest that adding the nuclear grade to the pathological diagnosis of invasive breast carcinoma may be clinically useful for predicting tumor behavior, for example aggressiveness, and for prognostication.

Loss of cell cohesion in breast cytology as a characteristic of neuroendocrine carcinoma.

OBJECTIVE To characterize a specific group of breast cancers displaying a scattered single cell pattern in cytology and correlate it with histologic and immunohistochemical findings. STUDY DESIGN Of 135 consecutive malignant breast cytologic specimens, 12 cases were selected for their scattered single cell pattern on aspiration cytology. Immunohistochemical staining for neuroendocrine markers and prognostic parameters was performed on paraffin sections of corresponding primary breast carcinomas. RESULTS In the smears of the 12 cases, highly cellular neoplastic cells with a single cell pattern were observed predominantly. The tumor cells had relatively wide, granular cytoplasm and a low to moderate nuclear/cytoplasmic ratio. Histologically, they were arranged mainly in relatively large, solid nests and occasionally contained a tubular pattern with small amounts of stromal tissue. Five of the 12 cases demonstrated neuroendocrine differentiation with a positive immunoreaction for chromogranin A and synaptophysin. Except for the small mean size of the tumors (P < .01), no significant differences were identified among the prognostic parameters, including a nodal status, estrogen receptor status, growth fraction by Ki-67 or immunoreactivity for c-erbB-2, as compared with the other 123 cases. CONCLUSION Loss of cell cohesion in breast cytology is a good morphologic marker for identifying neuroendocrine breast carcinoma.

Significance of hormone receptor status and tumor vessels in normal, hyperplastic and neoplastic endometrium.

The aims of this study were to identity the roles of tumor vessels and hormone receptor status in normal, hyperplastic, and neoplastic endometrium, and to explore their relationships with other prognostic factors of endometrial adenocarcinoma. Endometrial curettage specimens of proliferative phase and secretory phase endometrium, simple hyperplasia with or without atypia, complex hyperplasia with or without atypia, and grade 1 adenocarcinoma were examined for estrogen receptor alpha (ER alpha), progesterone receptor (PgR), Ki‐67 labeling index (LI), cyclin D1, microvessel density (MVD), and area of venules (AV) using an immunoperoxidase method. The results showed high levels of ER alpha in complex hyperplasia, and high levels of PgR in simple hyperplasia without atypia. Expression of ER alpha in the endometrium decreased in a stepwise manner from complex hyperplasia without atypia to grade 1 adenocarcinoma. Expression of PgR in the endometrium decreased in a stepwise manner from simple hyperplasia without atypia to grade 1 adenocarcinoma. In contrast, the expressions of Ki‐67 LI, cyclin D1, MVD and AV in the endometrium increased in a stepwise manner from normal, simple or complex hyperplasia with or without atypia to grade 1 adenocarcinoma. These changes may become irreversible on progression from simple or complex hyperplasia to neoplasia.