Mitsuyoshi Hirokawa

Observer variation of encapsulated follicular lesions of the thyroid gland

Although histologic definition of follicular thyroid lesions is readily available, application of the diagnostic criteria and personal experience may lead to disagreement among pathologists. To investigate interobserver variation in assessment of encapsulated follicular lesions, eight pathologists (four American and four Japanese) reviewed the same hematoxylin and eosin-stained slide of each of 21 cases of thyroid lesions showing encapsulation and follicular growth pattern. In 10% of the cases, there was complete agreement. At least seven pathologists agreed on the diagnosis in 29% of the cases, and at least six in 76% of the cases. American and Japanese pathologists agreed among themselves in 33% and 52% of cases, respectively. The frequency of diagnosis of adenomatous goiter among Japanese pathologists (31%) was considerably higher than that among American pathologists (6%). In contrast, the frequency of diagnosis (25%) of papillary carcinoma among American pathologists was considerably higher than that (4%) among Japanese pathologists. Our analysis revealed three main factors affecting observer variation: 1) interpretation of the significance of microfollicles intimately related to capillaries within the tumor capsule, 2) evaluation of what constituted the type of nuclear clearing indicative of papillary carcinoma, and 3) absence of clear morphologic criteria for separation of adenomatous goiter and follicular adenoma. To reduce observer variation of encapsulated follicular lesions, it will be necessary to provide more explicit criteria for diagnosis.

Cribriform‐morular variant of papillary thyroid carcinoma: a pathological and molecular genetic study with evidence of frequent somatic mutations in exon 3 of the β‐catenin gene

The cribriform‐morular variant (C‐MV), an unusual and peculiar subtype of papillary thyroid carcinoma (PTC), has been observed frequently in familial adenomatous polyposis (FAP)‐associated thyroid carcinoma and also in sporadic thyroid carcinoma. In this paper, five young women with the C‐MV of PTC, aged 22–34 years at cancer diagnosis, are reported; two of them had attenuated FAP. Grossly, one FAP‐associated tumour and one sporadic tumour were multicentric and the others were solitary. Histologically, the tumours were encapsulated and exhibited a combination of cribriform, follicular, trabecular, solid, and papillary patterns of growth, with morular areas. Immunohistochemically, the tumour cells showed cytoplasmic expression of thyroglobulin, neuron‐specific enolase, epithelial membrane antigen, high‐ and low‐molecular‐weight cytokeratins, vimentin, and bcl‐2 protein; nuclear expression of oestrogen and progesterone receptors, and retinoblastoma protein; and cytoplasmic and nuclear accumulation of β‐catenin. Germline mutations of the adenomatous polyposis coli (APC) gene were investigated using the protein truncation test in four subjects, including two FAP individuals. Germline APC mutation was identified in only one FAP patient with the multicentric C‐MV of PTC, who had a thymidine deletion at codon 512, resulting in a frameshift leading to a premature stop codon. No loss of heterozygosity of loci close to the APC gene was detected in tumour tissues from these four patients. Somatic mutation analysis of exon 3 of the β‐catenin gene (CTNNB1) revealed alterations in seven tumours from all five individuals: one at a serine residue (codon 29), three at amino acids adjacent to serine or threonine residues (codons 22, 39, and 44), and three at other amino acids (codons 49, 54, and 56). Moreover, each of two different tumours examined from two patients with the multicentric C‐MV of PTC, had different somatic mutations of the CTNNB1 gene. Taken together, these data suggest that accumulation of mutant β‐catenin contributes to the development of the C‐MV of PTC. Copyright

Induction Chemotherapy with Weekly Paclitaxel Administration for Anaplastic Thyroid Carcinoma

BACKGROUND Anaplastic thyroid carcinoma (ATC) has a very dire prognosis and no effective therapeutic strategies have been established for ATC patients, especially those with stage IVB or IVC. Our objective was to investigate the effectiveness of weekly paclitaxel administered as induction chemotherapy and to establish novel therapeutic strategies for ATC. METHODS We performed induction chemotherapy by weekly paclitaxel administration for patients with stage IVB (nine patients) and IVC (four patients) disease. Clinical and histological responses were assessed. Overall survival was compared with that of ATC patients with stage IVB (n = 50) and IVC (n = 13) treated without paclitaxel. RESULTS One patient demonstrated complete response (CR) and two demonstrated partial response (PR) in the stage IVB group (response rate: 33%), and one patient showed PR in stage IVC (response rate: 25%). Curative surgery and adjuvant therapy were performed for four patients with stage IVB, and 32 months after treatment, all the four are alive and free of disease. One CR patient and one stable disease patient were assessed as grade IV (complete remission) and grade III (nearly CR) on histological response, respectively. All four patients with stage IVC died of carcinoma within 8 months. Overall survival of stage IVB patients with induction chemotherapy was better (p = 0.0213) than that without the chemotherapy and also better (p = 0.0467) than those with chemotherapy other than paclitaxel. However, induction chemotherapy did not improve the overall survival of stage IVC patients (p = 0.2002). CONCLUSIONS Induction chemotherapy by weekly paclitaxel is a promising therapeutic strategy for stage IVB ATC patients. Responders can be expected to achieve long-term survival. We could not get significant difference of overall survival between stage IVC patients with or without weekly induction paclitaxel, although there were some cases that responded well.

Biological behavior and prognosis of familial papillary thyroid carcinoma

BACKGROUND Although the responsible genes have not yet been identified, it is known that the risk of nonmedullary thyroid carcinoma is elevated in individuals with 1st-degree relatives with nonmedullary thyroid carcinoma. However, it remains controversial whether the biological character of familial nonmedullary carcinoma (FNMTC) differs from that of sporadic carcinoma. In this study, we investigated the prevalence of familial papillary carcinoma and its biological behavior. METHODS Between 1987 and 2004, 6,015 patients underwent initial surgical treatment for papillary carcinoma at Kuma Hospital and 273 (4.5%) were classified as having familial carcinoma. We compared the biological characteristics including prognosis between familial and sporadic papillary carcinomas. RESULTS Disease-free survival and cause-specific survival rates of familial carcinoma did not differ from those of sporadic carcinoma. Familial papillary carcinoma showed multicentricity and recurrence to the thyroid more frequently than sporadic carcinoma. There were no differences in other clinicopathological parameters between the 2 groups. CONCLUSION Prognosis of patients with familial papillary carcinoma did not differ from that of those with sporadic papillary carcinoma. Although routine total thyroidectomy is recommended for familial papillary carcinoma, its therapeutic strategy can otherwise be the same as that for sporadic papillary carcinoma.

Hyalinizing Trabecular Tumors of the Thyroid Gland are Almost all Benign

In 1987, Carney et al reported 11 thyroid tumors with the following features: circumscription or encapsulation, trabecular architecture with intratrabecular hyalin and colloid, polygonal and spindle cells, nuclei with frequent grooves and cytoplasmic inclusions, occasional psammoma bodies, and a low mitotic rate. The neoplasms did not recur or metastasize during a follow-up period that averaged 10 years, and they were titled hyalinizing trabecular adenomas. Subsequently, the nuclear features of the neoplasm led to the introduction of 2 modified titles for it, hyalinizing trabecular tumor and hyalinizing trabecular neoplasm. Later, discovery of RET/PTC mutations in the tumor resulted in it being designated as a type of papillary thyroid carcinoma. We studied 119 neoplasms of the type outlined, collected over a 20-year period, for invasion, recurrence and metastasis, and obtained follow-up in 96% of the cases. One hundred eighteen tumors showed no evidence of aggressive behavior (capsular, vascular, and parenchymal invasion), local recurrence, or metastasis. One tumor showed vascular and capsular invasion, and pulmonary metastasis. We conclude that the overwhelming majority of hyalinizing trabecular tumors of the thyroid behave as benign neoplasms and that, at this time, hyalinizing trabecular adenoma is the most appropriate title for them.

Prognosis and prognostic factors of follicular carcinoma in Japan: importance of postoperative pathological examination.

BackgroundFollicular carcinoma is known to show a worse prognosis than papillary carcinoma because of distant metastasis in higher incidence. However, few studies have been published regarding the prognosis of follicular carcinoma patients in Japan, which prompted us to investigate this issue.MethodsWe examined the prognosis and whether and how various clinicopathological features have affected disease-free survival (DFS) and cause-specific survival (CSS) of 334 patients who underwent initial surgery for follicular carcinoma.ResultsIn 18 patients (5.4%), curative surgery could not be achieved because of distant metastasis at surgery in 17 patients and local extension in 1 patient. For 316 patients who underwent curative surgery, 5-year and 10-year DFS rates were 88.4% and 75.3%, respectively. Poorly differentiated carcinoma and widely invasive carcinoma, together with some conventional prognostic factors, predicted poorer DFS of patients. On multivariate analysis, poorly differentiated carcinoma was an independent prognostic factor for DFS. The 5-year and 10-year CSS rates for these 334 patients were 96.4% and 90.4%, respectively. Curative surgery and poorly differentiated carcinoma were recognized as independent prognostic factors.ConclusionsWe can hypothesize that follicular carcinoma in Japan is generally a nonaggressive disease with a good prognosis. However, because poorly differentiated or widely invasive carcinomas showed a worse prognosis, postoperative pathological examination is important in predicting patient prognosis.

The FOXE1 and NKX2-1 loci are associated with susceptibility to papillary thyroid carcinoma in the Japanese population

Background FOXE1 and NKX2-1 are two known genetic risk factors for the predisposition to sporadic papillary thyroid carcinoma (PTC) in Europeans, but their association in other ethnicities is still unknown. Objective We aim to examine the association of the two genes with Japanese sporadic PTC, which exhibits high BRAFV600E mutation rate. Methods 507 Japanese sporadic PTC cases and 2766 controls were genotyped for rs965513 (FOXE1) and rs944289 (NKX2-1). PTC cases were also examined for their BRAFV600E mutational status. Results The association of both rs965513 (p=1.27×10−4, OR=1.69, 95% CI 1.29 to 2.21) and rs944289 (p=0.0121, OR=1.21, 95% CI 1.04 to 1.39) with the risk of sporadic PTC was confirmed. Subgroup analysis based on the BRAF mutational status showed strong association of rs965513 with BRAFV600E-positive cases (p=2.26×10−4, OR=1.72, 95% CI 1.29 to 2.29), but not with BRAFV600E-negative cases (p=0.143, OR=1.52, 95% CI 0.87 to 2.65). However, there was no difference in the observed effect size between both subgroups. For rs944289, both subgroups showed marginal association (p=0.0585, OR=1.17, 95% CI 0.99 to 1.37 for BRAFV600E-positive cases; p=0.0492, OR=1.35, 95% CI 1.00 to 1.81 for BRAFV600E-negative cases). Conclusions Both FOXE1 and NKX2-1 were associated with the increased risk of sporadic Japanese PTC. No clear associations were observed for either SNP with BRAFV600E status.

Role of E-Cadherin, α-, β-, and γ-Catenins, and p120 (Cell Adhesion Molecules) in Prolactinoma Behavior

E-cadherin/catenin complex regulates cellular adhesion and motility and is believed to function as an invasion suppressor system. In a number of cancers, abnormal and reduced expression of E-cadherin/catenin complex is associated with tumor invasion and metastasis. Prolactinomas show frequent invasion on the surrounding structures, despite their histologically benign nature. Furthermore, gender-based differences in endocrine and surgical findings are found in patients with prolactinoma. To understand biological factors governing prolactinoma behavior, this study analyzed the expression of E-cadherin; α-, β-, and γ-catenins; p120; and cell proliferation marker MIB-1 labeling index in 13 invasive tumors (9 in men, 4 in women), 26 noninvasive tumors (4 in men, 22 in women), and 8 normal anterior pituitaries by immunohistochemistry. Immunostaining of E-cadherin; α-, β-, and γ-catenins; and p120 showed a membranous pattern of reactivity and generally stronger in normal pituitaries than in prolactinomas. Expression of E-cadherin and β-catenin was significantly lower in invasive than in noninvasive prolactinomas (P <.002 and P <.005, respectively), and reduced expression of E-cadherin and β-catenin was more frequent in invasive than in noninvasive prolactinomas (P <.001 and P <.05, respectively); in contrast, γ-catenin expression showed higher in invasive than in noninvasive prolactinomas (P <.05). Expression of E-cadherin was significantly lower in macroprolactinomas than in microprolactinomas (P <.01), and decreased expression of E-cadherin and β-catenin predicted high MIB-1 expression (P <.05). Moreover, the expression of E-cadherin and β-catenin was significantly lower in macroprolactinomas in men than in those in women (P <.01 and P <.02, respectively). No statistical correlations were observed between expression of α-catenin, p120, and clinicopathologic features. In conclusion, the reduction of E-cadherin and β-catenin expression was related to invasiveness and proliferative status of prolactinomas and correlated with the more aggressive behavior of prolactinomas in men compared with in women.

Secretory carcinoma of the breast: a tumour analogous to salivary gland acinic cell carcinoma?

Secretory carcinoma of the breast: a tumour analogous to salivary gland acinic cell carcinoma?

Extranodal tumor extension to adjacent organs predicts a worse cause-specific survival in patients with papillary thyroid carcinoma

BackgroundWe previously reported that massive extrathyroid extension has an independent prognostic value in patients with thyroid papillary carcinoma. However, tumor extension to adjacent organs can be observed not only in primary tumor but also in metastatic nodes. In this study we investigated the clinical significance of extranodal tumor extension to adjacent organs (nodal ex) in papillary thyroid carcinoma.MethodsWe classified all cases into three categories based on the degree of nodal ex: nodal ex0, no apparent extranodal tumor extension; nodal ex1, hard metastatic nodes with perinodal growth extending to adjacent organs, which require separation of the nodes from the organs; and nodal ex2, metastatic nodes with perinodal growth completely invading the adjacent organs and requiring excision of nodes together with these organs. We investigated the clinical significance of each grade in 1,692 patients who underwent initial surgery for papillary carcinoma between 1987 and 1995.ResultsThe presence of nodal ex was significantly linked to various clinicopathological features such as male gender, N1b, large number of metastatic nodes, pT4a, and distant metastasis. On univariate analysis, patients with either nodal ex1 or ex2 showed significantly worse disease-free and cause-specific survival rates, although these rates did not differ between patients with nodal ex1 and those with nodal ex2. Furthermore, multivariate analysis demonstrated that nodal ex independently predicts worse cause-specific survival of these patients.ConclusionsPresence of nodal ex significantly reflects the biologically aggressive behaviors of papillary carcinoma and has a prognostic value, especially for cause-specific survival of patients.