PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses

A PAX8-PPARgamma rearrangement has been recently identified in follicular thyroid carcinomas, but not in follicular adenomas or other thyroid tumors. We report here the analyses of PAX8-PPARgamma in a series of 118 thyroid tumors using a newly developed RT-PCR assay to detect this rearrangement in frozen and paraffin-embedded tissues and using immunostaining with a PPARgamma antibody. PAX8-PPARgamma was detected by RT-PCR in eight of 15 (53%) follicular carcinomas and two of 25 (8%) follicular adenomas but not in 35 papillary carcinomas (including 12 follicular variants), 12 Hurthle cell carcinomas, 12 Hurthle cell adenomas, two anaplastic carcinomas, one poorly differentiated carcinoma, or 16 hyperplastic nodules. The prevalence was higher in follicular carcinomas from patients with a history of radiation exposure (three of three). Strong, diffuse nuclear immunostaining with the PPARgamma antibody correlated with the presence of PAX8-PPARgamma detected by RT-PCR. Most sporadic follicular carcinomas positive for PAX8-PPARgamma were overtly invasive, whereas tumors lacking the rearrangement were predominantly minimally invasive. The two follicular adenomas positive for PAX8-PPARgamma had trabecular growth pattern and thick capsule, but no invasion, and thus may represent "pre-invasive" follicular carcinomas. The absence of PAX8-PPARgamma rearrangements in Hurthle cell tumors and papillary thyroid carcinomas highlights the differences in the molecular pathogenesis of these thyroid tumors.     

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。     

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。     

Histologic variants of papillary and follicular carcinomas associated with anaplastic spindle and giant cell carcinomas of the thyroid: an analysis of rhabdoid and thyroglobulin inclusions

We describe the histologic variants of papillary and follicular carcinomas associated with 109 spindle and giant cell carcinomas (SGCC) of the thyroid and determine the incidence of rhabdoid and thyroglobulin inclusions in these tumors. In addition, we searched for rhabdoid and thyroglobulin inclusions in 120 papillary carcinomas (PC) (all 15 variants included), 23 differentiated follicular carcinomas (DFC), (6 with insular pattern), 6 poorly differentiated follicular carcinomas (PDFC) and 34 follicular adenomas (FA). The following differentiated thyroid carcinomas coexisted with SGCC: 51 (46.8%) PC, (34 conventional type, 14 tall cell variant and 3 follicular variant), 6 (5.5%) DFC, 1 follicular carcinoma with insular pattern (0.9%), and 3 oncocytic carcinomas (2.8%). Eleven SGCC (10%) and 2 (33%) PDFC showed rhabdoid features, but lacked thyroglobulin inclusions. Thyroglobulin inclusions were found in 10 FA (29%), 8 (17%) follicular variants of PC and in 7 (30.4%) DFC. There were no rhabdoid inclusions in any of these differentiated thyroid tumors. Our findings support the hypothesis that most SGCC result from dedifferentiation or anaplastic transformation although the mechanisms that underlie this transformation remain unknown. The finding that only 1 (0.9%) SGCC was associated with follicular carcinoma with insular pattern contradicts the opinion that this tumor occupies an intermediate position between differentiated and anaplastic carcinomas. Rhabdoid features are markers of PDFC and SGCC while thyroglobulin inclusions are markers of FA and differentiated thyroid carcinomas with follicular phenotype.     

Discrimination of benign and malignant thyroid nodules by molecular profiling

BACKGROUND: The evaluation of thyroid nodules by fine-needle aspiration has been the standard for almost 30 years, despite significant shortcomings in sensitivity and specificity. Recent data from our laboratory have suggested that molecular profiling permits the discrimination of specific types of thyroid nodules. These studies were undertaken to determine whether molecular profiling can discriminate between benign and malignant thyroid nodules with the necessary sensitivity and specificity required of a screening test. METHODS: Molecular profiles of 11 papillary thyroid carcinomas, 13 follicular variant of papillary thyroid carcinomas, 9 follicular thyroid carcinomas, and 26 benign tumors (follicular adenomas and hyperplastic nodules) were analyzed by oligonucleotide microarray analysis. A gene list was created based on 45 samples. Seventeen samples were then added to the analysis as unknowns. A hierarchical clustering analysis was performed on all 62 samples to examine the groups for potential differences and the ability of the gene list to distinguish tumor types. RESULTS: Cluster analysis of all 62 samples produced 2 distinct groups, 1 containing the carcinomas and 1 containing the benign lesions. The sensitivity for a diagnosis of cancer was 91.7% with a specificity of 96.2% (3 follicular variant of papillary thyroid carcinomas clustered with the benign lesions). The cancer gene profiles contained both known cancer-associated genes (MET, galectin-3) and previously unidentified genes. CONCLUSIONS: Molecular profiling readily distinguishes between benign and malignant thyroid tumors with excellent sensitivity and specificity. Elucidated genes may provide insight into the molecular pathogenesis of thyroid cancer. Gene profiling may significantly enhance the evaluation of thyroid nodules in the future.     

Molecular analysis of Hurthle cell neoplasms by gene profiling

BACKGROUND: Though Hurthle cell tumors are considered a variant of follicular lesions, recent data have suggested that Hurthle cell carcinomas may be more closely related to papillary thyroid carcinomas (PTCs). These studies were conducted to determine if molecular profiling can enhance our understanding of Hurthle cell neoplasms. METHODS: Thirteen Hurthle cell tumors (9 adenomas, 4 carcinomas) were analyzed with the Affymetrix HU-95 gene chips. Molecular profiles obtained were compared to 14 follicular adenomas (FAs), 7 follicular carcinomas (FCs), 10 PTCs, 11 follicular variant PTCs, and 9 hyperplastic nodules. Hierarchical cluster analysis defined potential groupings and differences among samples. RESULTS: Hurthle cell carcinomas grouped with FCs 100% of the time. Surprisingly, Hurthle cell adenomas clustered with FCs when compared to FAs and FCs in 8/9 (88%) cases. All 13 Hurthle cell lesions migrated as a distinct group separate from PTCs and FVPTCs. Finally, all Hurthle cell lesions clustered with FCs, rather than PTCs, when compared to both groups. CONCLUSIONS: Molecular profiles of Hurthle cell adenomas and carcinomas are more similar to FCs than benign lesions or PTCs. Although Hurthle cell adenomas generally behave in a benign fashion, the molecular signature of these lesions suggests a more malignant phenotype.     

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.     

Galectin-3 expression in hyalinizing trabecular tumors of the thyroid gland

Galectin-3, a beta-galactoside-binding lectin, is overexpressed in many neoplasms and may be useful when differentiating between benign and malignant thyroid neoplasms. Recently, interest has focused on the classification and biologic behavior of hyalinizing trabecular tumors (HTTs). In this study we compared galectin-3 expression in a number of different thyroid neoplasms to gain insight into the biologic behavior of HTT. Formalin-fixed, paraffin-embedded tissues from 153 thyroid neoplasms were stained with a monoclonal antibody to galectin-3. These tumors included 58 HTTs, 60 papillary carcinomas, 21 follicular carcinomas, and 14 follicular adenomas. Reactivity was graded as negative, weak, or strong by three observers. The average patient age was similar in the patients with HTTs, papillary carcinomas, and follicular adenomas. The patients with follicular carcinomas were approximately a decade older than all other groups of patients. All groups of thyroid neoplasms occurred more frequently in female patients. Follow-up revealed metastatic disease in patients with papillary (36.6%) and follicular carcinomas (19%) but not in patients with follicular adenomas or HTTs. Galectin-3 immunostaining showed that 60% of the HTTs were negative or had weak (H) (1+) staining and 40% had strong (2-3+) staining. In the majority of the reactive cases, staining was diffuse and predominantly cytoplasmic. Fifty of the 60 (83%) papillary carcinomas and 11 of the 21 (52%) follicular carcinomas showed strong immunostaining. The immunostaining was also diffuse in the majority of papillary and follicular carcinomas. The strong immunoreactivity seen in most of the carcinomas was in contrast to the relatively weak or negative immunostaining in the majority of follicular adenomas (93%). The immunophenotype of HTT, as characterized by galectin-3 expression, is intermediate between that of benign and malignant thyroid tumors, suggesting that some tumors with strong staining may behave like carcinomas, although this was not noted in our cases. Our study suggests that the variable pattern of galectin-3 expression may reflect a difference in biologic behavior between HTT and papillary thyroid carcinoma.     

特殊病理类型甲状腺微小癌诊治

在甲状腺微小癌中乳头状癌最多见,其他少见的特殊病理类型有滤泡变异型、滤泡型、嗜酸细胞型、高细胞亚型、弥漫硬化压型等。对有明显的颈部淋巴结转移、甲状腺外浸润和远处转移的高危病人,理想的手术方式是甲状腺全或近全切除术+淋巴结清扫。甲状腺癌肿瘤直径<1 cm、单发病灶局限于腺叶内、无甲状腺外浸润、无颈部淋巴结转移、复发危险度低的病人,可以行甲状腺腺叶+峡部切除术。     

甲状腺乳头状癌组织学变型的临床生物学特性

目的 阐明甲状腺乳头状癌（papillary thyroid carcinoma，PTC）组织学变型的临床生物学特点。方法 选取我院自1974至1994年间收治的具有完整病历记录和随访观察的PTC病例505例，按国际最新甲状腺肿瘤的组织学分类标准重新分型，总结并分析各组织学变型的临床生物学特性。结果 所有变型中，弥漫硬化型发生率最高，达20．0％；弥漫滤泡型、柱状细胞型及大滤泡型发生率最低。高细胞型、弥漫滤泡型、柱状细胞型和弥漫硬化型颈部淋巴结转移率和侵出腺外发生率较高，预后差；乳头状微癌和大滤泡型颈部淋巴结转移率和侵出率则较低，预后好。按照颈淋巴结转移发生率的高低差异可将所有变型分为高转移变型组（高细胞型、弥漫滤泡型、柱状细胞型、弥漫硬化型）、中转移变型组（滤泡型、嗜酸性细胞型、实体状变型、间质高度增生呈结节状筋膜炎样型、透明细胞型、典型PTC）和低转移变型组（大滤泡型、乳头状微癌），颈淋巴结转移率分别为83．0％，55．5％及34．1％（P〈0．05）。结论 PTC各组织学变型的临床生物学特性存在一定差异。应细化外科处理原则，以使患者得到更加恰当的治疗。     

Encapsulated papillary neoplasms of the thyroid. A study of 14 cases followed for a minimum of 10 years

Fourteen cases of encapsulated papillary thyroid neoplasm in which extracapsular extension was not observed and a minimum of 10 years follow-up was available are herein presented. The cases were divided into three categories: encapsulated papillary carcinomas (five cases), which had cytologic features typical of papillary thyroid carcinoma (vesicular or indented nuclei) and an entirely or predominantly thick capsule with capsular invasion; encapsulated papillary neoplasms of undetermined malignancy (seven cases), in which the cytologic features were also typical of papillary carcinoma but the capsule was predominantly thin (less than 0.1 mm thick) or was thick without capsular invasion; and follicular adenomas with papillae (two cases), which resembled follicular adenomas cytologically (rounded, stippled nuclei and Hürthle cell change) but contained a significant number of papillary structures (both cases had an entirely or predominantly thin capsule). The only evidence of malignant behavior in the entire series was a cervical lymph node metastasis in one case of encapsulated papillary carcinoma; the "encapsulated papillary neoplasms of undetermined malignancy" were so labeled because other authors have reported "encapsulated papillary carcinomas without capsular invasion" and it was therefore thought that the malignant potential of this category is as yet best considered undefined.     

Hurthle cell neoplasm: our experience

Hurthle cell neoplasm is a rare form of thyroid tumors, comprising from 1.5% to 10% of all tumors. Hurthle cell nodules are clinically indistinguishable from other nodular thyroid diseases. The histologic features of Hurthle cell neoplasm don't allow us to exactly distinguish benign nodules from malignant ones. Accurate histologic valutation is possible and necessary for a correct diagnosis and therapy of Hurthle cell tumors. The adenomas usually exhibit a follicular pattern; the carcinomas include a subset of Hurthle cell tumors with different biological behavior, including malignant follicular variants and papillary ones. The authors are in favour of total thyroidectomy for carcinomas and lobectomy plus isthectomy for adenomas; in case of carcinomas, the lymphadenectomy reduces the incidence of local relapse and is necessary in case of lymphnode involvement. Adjuvant radiation therapy is successful in preventing recurrences, in symptomatic metastates as palliative therapy and control recurrence of advanced resected tumors.     

Analysis of ultrasound B-mode histogram in thyroid tumors

B-mode histograms of preoperative ultrasound texture were correlated to final pathological diagnoses and findings in 50 thyroid tumors (18 follicular adenomas, 6 follicular carcinomas and 26 papillary carcinomas) and 10 cases without any thyroid disease. Histograms were taken in the region of interest (ROI) and in the control area of the normal thyroid tissue. The following parameters, after subtracting the statistics of the control region from that of ROI, were evaluated; the difference of mean (D1), of standard deviation (D2), of skewness (D3), and of krutosis (D4). Likewise, Maharanobis distance (MD) was also studied. D1 was lower in papillary carcinomas than in follicular adenomas, and diminished by the relative proportion of some pathological findings, D2 and D3 of papillary carcinomas was higher than those of follicular adenomas. MD, having a significant correlation to D1 (r = -.8), revealed similar relationship with pathology as that of D1. No significant difference was observed between normal thyroid tissue and follicular adenoma, nor between follicular adenoma and follicular carcinoma in any parameter. MD showed the best correlation to malignancy. The criterion which judges the the tumor with D1 less than -2.5, or D2 more than 1 to be malignant, was expected to have sensitivity of 83% and specificity of 88%.     

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??Management for rare pathological subtype case of thyroid microcarcinoma LI Xiao-xi. Department of Vascular-Thyroid-Breast Surgery??the First Affiliated Hospital??Sun Yat-sen University??Guangzhou 510080??China
Abstract Papillary thyroid microcarcinoma is the most common type of thyroid microcarcinoma. Other uncommon variants have been described including follicular variant papillary thyroid microcarcinoma??follicular thyroid microcarcinoma??Hurthle cell microcarcinomas??tall cell variants??diffuse sclerosing variant and so on. Total/near total thyroidectomy with neck dissection may be the optimal surgical procedures for high-risk thyroid microcarcinoma patients who have gross lymph node metastasis??extrathyroid involvement and distant metastasis at presentation. Loboisthmusectomy may be a sufficient treatment of choice for patients with low-risk thyroid microcarcinoma when thyroid cancer less than 1 cm??unifocal??intrathyroidal??without extrathyroid invasion and lymph node metastasis.     

Follicular Histotypes of Oncocytic Thyroid Carcinomas Do Not Carry Mutations of the <Emphasis Type="Italic">BRAF</Emphasis> Hot-spot

Background The BRAF V600E mutation is the most prevalent genetic aberration in papillary thyroid carcinomas (PTCs), and it is found exclusively in RET/PTC-negative tumors. In oncocytic (Hürthle cell, oxyphilic) thyroid tumors, the presence of RET/PTC rearrangements is associated with either the conventional papillary histotype or the “solid” Hürthle cell tumors, whereas all predominantly follicular oncocytic carcinomas do not harbor RET/PTC chimeras. Although 12% of tumors of the follicular variant of PTC carry BRAF mutations, none of the few oncocytic follicular thyroid adenomas (oncoAd) or carcinomas (oncoFTC) published worldwide tested positive. An aspired molecular-based classification of oncocytic thyroid tumors is in need of additional evidence on BRAF mutations in the follicular histotype. Methods A series of 44 oncocytic thyroid tumors with well-documented clinicopathological data was subjected to BRAF mutation analysis (complete exon 15) by automated sequencing. Results The series of oncocytic thyroid tumors consisted of 21 adenomas (oncoAds: 17 females, 4 males; mean age, 54.5 years; range, 27–80 years), 20 follicular carcinomas (oncoFTCs: 14 females, 6 males; mean age, 61.4 years; range, 39–80 years), and 3 “classic” papillary carcinomas (oncoPTCs: 3 females; mean age, 58.1 years; range, 46–70 years; 3x T2 tumors). The follicular variants of oncocytic cancers are divided into 11x T2, 5x T3, and 4x T4 tumor stages (International Union Against Cancer [UICC] TNM 5th edition). None of the 44 neoplasms of the presented series demonstrated genetic alterations in the BRAF hot-spot region (exon 15, codons 599–601). Congruently, 0/10 oncoAd and 0/20 oncoFTC described in the literature so far carried BRAF V600E mutations. Conclusions Our results add to the evidence that, in contrast to follicular variants of oncoPTCs, predominantly follicular oncocytic thyroid tumors harbor neither RET/PTC rearrangements nor BRAF mutations. Furthermore, the findings support the concept that oncocytic neoplasms of the thyroid gland are oncocytic counterparts of the respective histotype (adenoma, FTC, PTC, or poorly differentiated thyroid carcinoma) rather than a separate tumor entity. Molecular characterization of oncocytic thyroid malignancies for RET/PTC or BRAF genetic alterations may help with (preoperative) classification and prognostic evaluation of these tumors.     

Downregulation of p27KIP1 and Ki67/Mib1 labeling index support the classification of thyroid carcinoma into prognostically relevant categories.

The cyclin-dependent kinase inhibitor p27KIP1 has been proposed as a valuable prognostic indicator for a variety of human neoplasms. Immunohistochemical reactivity for p27KIP1 and the proliferation marker Ki67/Mib1 were investigated in 90 thyroid carcinomas of follicular cell origin. The neoplasms were divided into three prognostic groups on the basis of their morphologic features: group 1, well-differentiated papillary or follicular carcinomas with favorable pathologic features (43 papillary carcinomas and 4 minimally invasive follicular carcinomas); group 2, papillary or follicular carcinomas with unfavorable pathologic features (21 poorly differentiated carcinomas and 2 papillary carcinomas, tall cell variant); and group 3, undifferentiated, or anaplastic, carcinomas. p27KIP1 expression (p = 0.007) and Ki67/Mib1 labeling index (p = 0.02) showed a strong correlation with the subdivision of the thyroid carcinomas in the three prognostic groups with a significant linear trend for tumors with low p27KIP1 (p = 0.002) and high Ki67/Mib1 labeling index (p = 0.005) to segregate into the unfavorable categories (groups 2 and 3). Low p27KIP1 expression, but not cellular proliferation, was related to adverse prognostic factors, such as large tumor size (p = 0.03) and extrathyroidal extension (p = 0.01), but the correlation was not independent of the subdivision in the three groups. Low p27KIP1 expression (p = 0.03) and high proliferative rate (p = 0.02) were associated with poor survival, reflecting the close association between patient morbidity and mortality rates and tumor differentiation. No significant association could be seen between p27KIP1 or cellular proliferation and clinicopathologic parameters (e.g., age, sex, tumor size, extrathyroidal extension, vascular invasion, lymph node metastases, distant metastases, tumor stage, and survival rate) within any of the groups, or the histologic diagnosis of papillary versus follicular carcinoma irrespective of their degree of differentiation. Modulation of p27KIP1 and cellular proliferation patterns in thyroid carcinoma correlate with tumor differentiation and support the morphologic classification of thyroid carcinoma into prognostically relevant categories.     

Thyroid disorders. Part III: neoplastic thyroid disease.

This paper is part III of the series on thyroid disorders. Thyroid tumors are the most common endocrine neoplasms. Most of these tumors are benign hyperplastic or colloid nodules or benign follicular adenomas. However, 5% to 10% of the lesions that come to medical attention are carcinomas. A major clinical challenge is establishing which nodules are hyperplastic, benign, or malignant. History, clinical findings, ultrasonography, and fine-needle aspiration biopsy are the mainstays for diagnosis. There are 3 main histologic types of thyroid cancer: differentiated, medullary, and anaplastic. Differentiated lesions are subdivided into papillary, follicular, and Hurthle cell carcinomas. In addition, primary lymphoma may occur in the thyroid gland and other cancers may metastasize to the thyroid. An important neoplastic syndrome, multiple endocrine neoplasia type 2 (MEN2), involves medullary carcinoma of the thyroid gland. In 2002 there were 10 cases of thyroid cancer per 100 000 population. During the past 10 years the rate of thyroid cancer has been increasing 5% per year. The overall 10-year survival for papillary carcinoma is 80% to 90%, follicular carcinoma 65% to 75%, and medullary carcinoma 60% to 70%. The prognosis for anaplastic carcinoma is very poor and 5-year survival is rare. The dentist by inspection and palpation of the neck in the area of the thyroid gland may detect single or multiple lesions that may be benign or malignant. Patients with identified nodules or enlarged thyroid glands should be referred for diagnosis and treatment. Patients with thyroid cancer will benefit from the early detection and treatment of their lesions as early detection can lead to a cure or prolongation of their life.