Measurement of cellular DNA content in thyroid tumors by the flow cytometer

Cellular DNA contents measured by flow cytometer were analysed in relation to histopathological classification and clinicopathological findings in 94 patients with thyroid tumors. The DNA determination was carried out on both tumor tissues and surrounding thyroid tissues. As an indicator of tumor growth, proliferative index (PI) and DNA index were calculated from DNA histograms. The PI value (mean +/- SD) was 32.5 in medullary carcinoma, 31.3 +/- 10.2 in follicular carcinoma, 28.2 +/- 6.2 in papillary carcinoma, 21.6 +/- 4.4 in follicular adenoma, and 20.6 +/- 4.4 in adenomatous goiter, respectively, whereas the value in normal thyroid tissues was 4.1 +/- 2.2. PI values in the surrounding thyroid tissues in cases of follicular and papillary carcinomas were significantly (p less than 0.01) lower than those of the corresponding cancer tissues, but they were higher than that of the normal tissues. The DNA index and frequencies of aneuploidy were 1.15 and 50.0% in medullary carcinoma; 1.25 +/- 0.27 and 66.7% in follicular carcinoma; 1.19 +/- 0.25 and 64.2% in papillary carcinoma; 1.01 +/- 0.04 and 9.3% in follicular adenoma; and 1.00 +/- 0.00% in adenomatous goiter. The result implies that PI value and DNA index are relatively correlated with clinicopathological criteria of malignancy of individual thyroid tumors, and they may become a putative tool for determination of the biological malignancy.     

Solitary fibrous tumor of the thyroid gland: report of seven cases.

Solitary fibrous tumor is a soft tissue neoplasm initially described in the pleura but subsequently reported in a wide variety of locations. The clinical behavior is usually benign, but the existence of aggressive cases has been documented both in the pleura and in extrapleural sites. In this report clinical and pathologic features of seven solitary fibrous tumors of the thyroid gland are presented. Patients' ages ranged from 43 to 64 years (mean 52 years), and tumor sizes varied from 2 to 6 cm. Grossly, the tumors were white-tan and well circumscribed. Microscopically, there was a variegated, wavy, storiform, hemangiopericytic or desmoid-like arrangement of spindle cells. Trapped thyroid follicles within the tumor and peripheral jagged tumor infiltration among follicles were common. There was immunohistochemical reactivity for CD34, CD99, and bcl-2, and ultrastructural analysis of one tumor was consistent with a fibroblastic lineage. The differential diagnosis included other benign and malignant mesenchymal tumors of the thyroid, spindle cell follicular adenoma, Riedel's thyroiditis, the spindle cell, and paucicellular variants of anaplastic carcinoma, papillary thyroid carcinoma with exuberant nodular fasciitis-like stroma, and the spindle epithelial tumor with thymus-like differentiation. The cumulative data of 13 cases (comprised of the seven present cases and the six previously reported) suggest a benign clinical behavior for thyroid SFT.     

Ornithine decarboxylase activity and polyamine levels in human thyroid tumor tissue

Production of polyamines such as putrescine (PUT), spermidine (SPD) and spermine (SPM) primarily from ornithine by ornithine decarboxylase (ODC) is correlated with cell proliferation. Polyamine levels and ODC activities were measured to determine the degree of biological malignancy in 186 thyroid tumor tissues. Carcinoma showed significantly higher ODC activity and higher levels of PUT, SPD and SPM than benign tumors. PUT levels showed 2.28 nmol/mg protein in anaplastic carcinoma, 0.66 in papillary carcinoma, 0.11 in follicular adenoma, 0.06 in adenomatous goiter and 0.04 in normal thyroid tissue. Anaplastic and papillary carcinomas showed higher PUT/SPD and SPD/SPM ratios than benign tumors. Poorly differentiated carcinoma showed significantly higher PUT level and PUT/SPD and SPD/SPM ratios than well differentiated carcinoma. No correlation was found among polyamine levels, ages and sex in papillary carcinoma. In female patients with papillary carcinoma, no significant difference in polyamine levels was observed between patients above and below 50 years old. These results suggest that ODC activity and polyamine levels may provide useful information to determine the degree of biological malignancy of thyroid tumors.     

巨大甲状腺肿临床诊治体会

【摘要】〓目的〓总结巨大甲状腺肿围手术期处理的经验。方法〓回顾性分析总结我院甲状腺专业组2011年1月~2014年6月收治的67例巨大甲状腺肿患者的临床资料,所有患者均采用手术治疗,分析和总结临床疗效、手术治疗相关要素和手术要点。结果〓67例均顺利行手术治疗并康复出院,3例出现暂时性喉上神经麻痹,5例出现低钙血症,随访3个月均恢复正常。术后病理报告显示:34例为毒性弥漫性甲状腺肿,23例为结节性甲状腺伴纤维化、钙化,3例为毒性结节性甲状腺肿,3例为结节性甲状腺肿并慢性甲状腺炎,2例为甲状腺滤泡性腺癌,2例为甲状腺高功能腺瘤。结论〓个体化的术前准备、轻柔精细的解剖操作,是手术成功的重要因素。     

Measurement of plasma calcitonin gene-related peptide (CGRP) level in patients with thyroid disease

To elucidate the pathophysiology of CGRP in patients with medullary thyroid carcinoma (MTC), we measured the plasma CGRP level in patients with thyroid disease employing RIA. The plasma CGRP level (normal level 12.7 pg/ml) was elevated in all five preoperative patients with MTC, ranging from 128 pg/ml to 2010 pg/ml, and in ten of 17 postoperative patients who indicated possible recurrence. On the other hand, CGRP levels showed low frequencies of elevation in 96 patients with other thyroid tumors (anaplastic carcinoma, malignant lymphoma, follicular adenoma and adenomatous goiter), subacute thyroiditis, chronic thyroiditis and Graves' disease. Provocation test (calcium gluconate plus pentagastrin) in 12 MTC patients showed that, although the CGRP level fluctuated in parallel with the calcitonin level, the elevation rate (maximum level after administration/basal level) of CGRP was lower than that of calcitonin. Particularly, the rate of elevation of CGRP in three virulent and advanced patients with poorly differentiated MTC was below 2.0, while that in nine patients with well-differentiated MTC ranged from 2.8 to 23.3. These results suggest that CGRP may be a humoral marker of MTC and is possibly related to the degree of malignancy.     

A case of anaplastic carcinoma of the mediastinal goiter]

We reported a case of anaplastic carcinoma of mediastinal goiter. The initial symptom was hoarseness, and thyroid scintigram and venogram revealed mediastinal thyroid malignant tumor, although cervical tumor could not be palpated. Operation was performed with median sternotomy. The size of the tumor was 8 x 6 x 3cm. Histological examination showed papillary adenocarcinoma of left lower pole of the thyroid gland which was transformed into anaplastic carcinoma and extended to the mediastinal cavity. Anaplastic carcinoma of mediastinal goiter is very rare, and our case showed anaplastic transformation from papillary adenocarcinoma.     

Cytopathological review of patients that underwent thyroidectomies based on the diagnosis of papillary thyroid carcinoma by fine needle aspiration cytology but were later found to have benign tumors by histopathology

Purpose

The aim of this study is to evaluate the specificity of diagnosing PTC by fine needle aspiration (FNA) cytology.

Methods

This study retrospectively reviewed the cytopathological reports of 1066 patients that underwent thyroidectomy based on a diagnosis of PTC by FNA between January 1993 and December 2008. This study re-evaluated the cytology and histopathology of the patients that received false positive diagnoses of PTC by FNA.

Results

Ten patients (0.9 %) received false positive diagnoses of PTC by FNA. Three patients were overdiagnosed as having PTC by FNA cytology. In contrast, the nuclear features of PTC in the other seven cases were confirmed by the retrospective reviews of the patients’ FNA cytology. Three of the seven patients showed follicular structures in their resection specimens, thus resulting in a diagnosis of either adenomatous goiter or follicular adenoma. However, PTC could not be diagnosed by histopathology in the remaining four patients, even though the histopathology showed the nuclear features of PTC.

Conclusions

Most cases of PTC can be easily diagnosed by cytological and morphological atypia with certain limitations. The difficulty in diagnosing PTC by cytology is because the pathological features of PTC also occur in some benign thyroid tumors. Therefore, immunohistochemical or molecular biological approaches must be combined with current cytological diagnostic techniques for the diagnosis of PTC.     

Clinical Relevance of Vascular Endothelial Growth Factor for Thyroid Neoplasms

Angiogenesis is of vital importance during the development and progression of solid tumors. Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis and could be produced by some cancer cells. To investigate the clinical relevance of VEGF in the tumorigenesis of human thyroid, an immunohistochemical study was performed on archival materials of follicular adenomas (n= 13), Hürthle cell adenomas (n= 6), papillary carcinomas (n= 76), follicular carcinomas (n= 12), Hürthle cell carcinomas (n= 2), and anaplastic carcinomas (n= 8). Patterns of VEGF expression were analyzed in relation to histologic subtypes of thyroid tumors and were correlated to biologic indicators of papillary carcinoma. All papillary carcinomas and Hürthle cell neoplasms revealed a strong, diffuse staining reaction, whereas anaplastic carcinoma usually exhibited weak and infrequent immunoreactivity. VEGF levels were usually higher in follicular adenomas than in follicular carcinomas. With regard to prognostic value, VEGF expression did not correlate with tumor size, extent of invasion, or scores on the AGES system (i.e., patient age, tumor size, histologic grade, tumor extent, distant metastasis) or the MACIS system (i.e., metastasis, age, completeness of resection, invasion, tumor size) for papillary carcinomas (p > 0.05, respectively). The results of the current study indicate that VEGF may play a role in the development of human thyroid cancer. Determination of the angiogenic phenotype may have limited prognostic value for patients with papillary carcinoma.     

Establishment,Characterization and Comparison of Seven Authentic Anaplastic Thyroid Cancer Cell Lines Retaining Clinical Features of the Original Tumors

Background

Anaplastic thyroid cancer (ATC) is thought to often be transformed from pre-existing differentiated thyroid cancer. It is one of the most aggressive malignancies and has a dismal prognosis due to its resistance to multimodal therapies. Basic exploratory studies using authentic ATC cell lines that retain its clinical features are necessary. We investigated the characteristics of seven ATC cell lines newly established at our institute to confirm their possible utility for basic studies.

Methods

Seven distinct cell lines from six patients were established. Their molecular characteristics and sensitivities to cytotoxic anti-cancer drugs were investigated and compared with each other, and with the clinical features of the original tumors.

Results

All cells showed extensive chromosomal abnormality and Pax8 expression, indicating human thyroid follicular cell origin. Vascular endothelial growth factor was secreted from all cells, suggesting possible candidacy for targeted therapy. Vimentin was expressed, but E-cadherin expression was lost in all cells but OCUT-1C, which showed different features from those of OCUT-1F derived from the same tumor, suggesting a mixture of cancer cell clones with various degrees of differentiation within a single ATC tumor. Cells were likely to show sensitivity for taxanes, indicating the usefulness of taxanes as the first-line chemotherapy. OCUT-2, a cell line with both B-Raf and PI3 KCA mutation, demonstrated the importance of molecular target-oriented therapy.

Conclusions

Basic studies using authentic ATC cell lines retaining the clinical features of the original tumor are useful models for investigating the mechanism of anaplastic transformation and exploring novel therapeutic strategies.     

CD10在甲状腺疾病中的表达及意义

目的研究CD10在甲状腺疾病中的表达及意义。方法收集70例甲状腺良、恶性病变组织,其中15例滤泡性腺瘤、15例腺瘤性甲状腺肿、30例乳头状癌和10例滤泡性癌。采用免疫组织化学的方法检测CD10在上述病变中的表达。结果9例滤泡型乳头状癌中,7例表达CD10,CD10阳性率为77％。10例滤泡性癌中,8例表达CD10,阳性率为80％。而在滤泡性腺瘤和腺瘤性甲状腺肿及21例普通型乳头状癌组织中CD10均不表达。CD10在滤泡型乳头状癌和滤泡性癌中的阳性率显著高于滤泡性腺瘤和腺瘤性甲状腺肿中的阳性率（P〈0．01）。结论对CD10表达的检测有助于对甲状腺滤泡性癌和滤泡型乳头状癌的诊断。     

Identification of Differentially Expressed MicroRNA in Parathyroid Tumors

Background

The molecular factors that control parathyroid tumorigenesis are poorly understood. In the absence of local invasion or metastasis, distinguishing benign from malignant parathyroid neoplasm is difficult on histologic examination. We studied the microRNA (miRNA) profile in normal, hyperplastic, and benign and malignant parathyroid tumors to better understand the molecular factors that may play a role in parathyroid tumorigenesis and that may serve as diagnostic markers for parathyroid carcinoma.

Methods

miRNA arrays containing 825 human microRNAs with four duplicate probes per miRNA were used to profile parathyroid tumor (12 adenomas, 9 carcinomas, and 15 hyperplastic) samples normalized to four reference normal parathyroid glands. Differentially expressed miRNA were validated by real-time quantitative TaqMan polymerase chain reaction (PCR).

Results

One hundred fifty-six miRNAs in parathyroid hyperplasia, 277 microRNAs in parathyroid adenoma, and 167 microRNAs in parathyroid carcinomas were significantly dysregulated as compared with normal parathyroid glands [false discovery rate (FDR) < 0.05]. By supervised clustering analysis, all parathyroid carcinomas clustered together. Three miRNAs (miR-26b, miR-30b, and miR-126*) were significantly dysregulated between parathyroid carcinoma and parathyroid adenoma. Receiver-operating characteristic curve analysis showed mir-126* was the best diagnostic marker, with area under the curve of 0.776.

Conclusions

Most miRNAs are downregulated in parathyroid carcinoma, while in parathyroid hyperplasia most miRNAs are upregulated. miRNA profiling shows distinct differentially expressed miRNAs by tumor type which may serve as helpful adjunct to distinguish parathyroid adenoma from carcinoma.     

CD10表达在甲状腺滤泡性癌和滤泡型乳头状癌诊断中的作用

目的研究CD10表达在甲状腺滤泡性癌和滤泡型乳头状癌诊断中的作用。方法收集70例甲状腺良、恶性病变组织，其中包括15例滤泡性腺瘤、15例腺瘤性甲状腺肿、30例乳头状癌（包括9例滤泡型乳头状癌）和10例滤泡性癌，采用免疫组织化学方法检测CD10在上述组织中的表达。结果9例滤泡型乳头状癌中，7例表达CD10（77．8％），10例滤泡性癌中8例表达CD10（80．0％）；CD10在非滤泡型乳头状癌、滤泡性腺瘤、腺瘤性甲状腺肿和正常甲状腺组织中均不表达。结论对CD10表达的检测有助于对甲状腺滤泡性癌和滤泡型乳头状癌的诊断。     

Cytoplasmic accumulation of alpha-catenin in thyroid neoplasms

BACKGROUND: Alpha-catenin (alpha-cat) is one of the anchoring proteins of E-cadherin. It has been shown that deviation in its function may alter the cadherin-catenin complex leading to disturbed cell-cell adhesion. Immunohistochemical studies have shown that cytoplasmic localization of alpha-cat in tumors is associated with aggressive behavior. In this study, we evaluated the expression of alpha-cat in various thyroid tumors by immunohistochemical analysis. METHODS: Fifty cases were selected:18 papillary carcinoma classic type (PTC), 9 follicular variant of PTC (FVPTC), 6 follicular carcinoma (FCA), 4 anaplastic carcinoma (ACA), 8 follicular adenoma (FA), 3 nodular goiter (NG), and 2 lymphocytic thyroiditis (LT). The staining reaction was classified as membranous, cytoplasmic, or both. The intensity of the staining was graded as negative (0), weak (+), moderate (++), and strong (+++). RESULTS: Staining along the cell membrane was observed in 36 (72%) and cytoplasmic expression was present in 28 (57%) cases. The cytoplasmic staining was more commonly seen in malignant lesions; it was more common in PTC (78% of all PTC) than follicular patterned lesions (FVPTC, FCA). All cases of ACA (4 of 4) showed only cytoplasmic expression. No correlation was found between lymph node involvement and alpha-cat staining patterns. CONCLUSIONS: Cytoplasmic expression of alpha-cat is more common in (1) malignant lesions of thyroid and (2) PTC than FVPTC and FCA. The lack of membrane and presence of cytoplasmic expression suggest a role of alpha-catenin in the aggressive biology of ACA.     

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.     

Fluorine-18-fluorodeoxyglucose positron emission tomography in the preoperative assessment of thyroid nodules in an endemic goiter area

BACKGROUND: The aim of this study was to evaluate the usefulness of fluorine-18-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) in the preoperative assessment of suspicious thyroid nodules. METHODS: A total of 43 patients were examined before surgical resection. In all patients, imaging was obtained at 70 minutes after the intravenous administration of 180 MBq (18)F-FDG. Standard uptake values (SUVs) were calculated. RESULTS: A total of 16 patients with thyroid carcinomas (11 papillary, 3 follicular, 2 anaplastic), 23 thyroid adenomas (11 microfollicular, 10 Hurthle cell, 2 macrofollicular), and 4 patients with degenerative goiter were found. (18)F-FDG uptake in Hurthle cell adenoma, thyroid cancer, microfollicular adenoma, degenerative goiter, and macrofollicular adenoma was 4.4 +/- 2.2, 3.7 +/- 1.9, 1.6 +/- 0.3, 1.2 +/- 0.2, and 0.9 +/- 0.1, respectively. Significant differences were observed between thyroid carcinomas and both microfollicular adenomas and degenerative goiters (P < 0.05), and between Hurthle cell adenomas and both microfollicular adenomas as well as degenerative goiter (P < 0.05). For diagnosis of thyroid carcinoma, 100% sensitivity, 63% specificity, and 100% negative predictive value was found when a cutoff value for SUV of 2 was used. CONCLUSIONS: Our results indicate that thyroid carcinomas, in contrast to most benign thyroid nodules, demonstrate significantly increased glucose metabolism. (18)F-FDG PET is unlikely to differentiate successfully all benign tumors from malignant tumors, but it can help select patients who need surgery, especially if cytology is inconclusive or malignancy cannot be excluded.     

Squamous cells in the human thyroid gland

Squamous epithelium in the thyroid, which may be basaloid, epidermoid, or truly squamous, may be derived from several sources. In the normal thyroid, usually rests of one type or another are responsible for these cell nests. Thus, thymic or ultimobranchial remanants may be found in the lateral lobes of normal thyroid glands. Maldevelopment or excessive descent of thyro-glossal duct remnants may be responsible for squamous epithelial cysts noted in the central portions of the thymus, especially in the isthmus. In diseased thyroids, the most likely derivation of squamous or epidermoid epithelium is through metaplasia of follicular epithelial cells. Thus, in adenomatous goiter and various types of thyroiditis as well as follicular derived neoplasms, such a derivation is most likely. In tumors containing malignant squamous epithelium (adenoacanthoma, adenosquamous carcinoma, or pure squamous carcinoma) there is a range of such lesions, and since many of them appear to be derived from follicular epithelium, it is most likely that squamous metaplasia which has undergone malignant transformation has occurred in these neoplasms.     

Pathohistologic and immunohistochemical characteristics of thyroid carcinoma

Numerous pathohistologic criteria, difficulties and pitfalls in the process of diagnosing of thyroid carcinoma are discussed. Benign hyperplastic papillae may be present in colloidal cystic goiter and hyperplastic goiter. These structures are lined by cells with normochromatic nuclei and do not disturb the thyroid tissue architecture. Papillae in papillary thyroid carcinoma have cells with ground-glass, hypochromatic nuclei. Follicles inspissated in capsula of follicular or even colloidal adenoma may be evaluated as capsular invasion--diagnostic feature of follicular carcinoma. Undifferentiated thyroid carcinoma is sometimes similar to fibrosarcoma and reveal cellular pleomorphism, anaplasia and numerous foci of necrosis. Medullary thyroid carcinoma with scanty stromal amyloid, its papillary variant and carcinoid-like histologic type consist of oval cells with eosinophilic cytoplasm and dark nuclei.     

Classification, staging, prognostic factors and risk factors in thyroid carcinoma

Thyroid carcinomas arise from follicular cells (papillary, follicular, Hurthle, anaplastic), parafollicular cells (medullary) and stroma (lymphoma, sarcoma). Gradation and prognostic factors are different for every one of histological type. Most patients with papillary and follicular thyroid cancer have an excellent prognosis. At the other extreme is anaplastic thyroid cancer whose usual mean survival can be measured in months. Exposure to external radiation and living in endemic goiter area increase the frequency of thyroid cancer. Medullary thyroid carcinoma is often familial and may occur in associations with the multiple endocrine neoplasia syndromes.