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.     

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.     

Encapsulated papillary oncocytic neoplasms of the thyroid: morphologic, immunohistochemical, and molecular analysis of 18 cases

Encapsulated papillary oncocytic neoplasms (EPONs) of the thyroid are rare tumors, whose relationship to other thyroid tumors has not been thoroughly elucidated. Earlier, they have been regarded as variants of papillary thyroid carcinoma (PTC), hyperplastic lesions, and follicular neoplasms. Eighteen EPONs were retrieved from our surgical pathology files and reviewed for defining morphologic features. Cases having the typical nuclear features of PTC were excluded. Immunohistochemistry (IHC) for CK19, HBME1, and CD56 was carried out. Microdissection, polymerase chain reaction, and sequencing of exon 15 of the BRAF gene were completed. Cases were evaluated for rearranged in transformation/papillary thyroid carcinoma RET/PTC rearrangement by fluorescent in situ hybridization (FISH). The majority of the tumors exhibited a distinctive histologic appearance. They were composed of true papillae lined by a single layer of predominantly cuboidal cells with oncocytic cytoplasm; hobnailing was typically prominent. Three tumors showed taller cells with uniformly apical nuclei and no hobnailing. Ten of 18 cases showed vascular and/or capsular invasion; hence, if the diagnostic criteria used to evaluate follicular neoplasms are applied, more than half of the tumors would be considered minimally invasive carcinomas. No cases were immunoreactive with antibodies to HBME1, whereas only 1 of 13 was immunoreactive for CK19. Six of 7 interpretable cases were immunoreactive for CD56. No BRAF point mutations or RET/PTC rearrangements were identified in the examined cases. All patients were alive at the time of last follow-up and no locally recurrent disease had been reported; however, 1 case was remarkable for a lymph node metastasis. Our results confirm that EPONs are histologically, immunohistochemically, and molecularly distinct from papillary thyroid carcinoma and seem to be most related to follicular neoplasms.     

Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas

Papillary carcinoma is the most common type of thyroid malignancy. It has been recently shown that these tumors commonly have one of three genetic alterations: BRAF point mutations, RET/PTC rearrangements, or RAS point mutations. In this study, we analyze the relationship between these alterations and the microscopic features of papillary carcinomas, their clinical features, and prognostic characteristics. Ninety-seven papillary carcinomas were studied; in all cases, frozen tissue was available for nucleic acid extraction. Of 96 unselected cases, 42% were positive for BRAF, 18% for RET/PTC, and 15% for RAS mutations. Morphologic features were evaluated in detail in 61 cases and 6 characteristic nuclear features and 3 additional microscopic features were assessed quantitatively. At least 4 nuclear features were found in each tumor, with nuclear pseudoinclusions being the least frequent finding in all mutation groups. BRAF mutations were associated with older patient age, typical papillary appearance or the tall cell variant, a higher rate of extrathyroidal extension, and more advanced tumor stage at presentation. RET/PTC rearrangements presented at younger age and had predominantly typical papillary histology, frequent psammoma bodies, and a high rate of lymph node metastases. Tumors with RAS mutations were exclusively the follicular variant of papillary carcinoma and correlated with significantly less prominent nuclear features and low rate of lymph node metastases. These findings demonstrate that BRAF, RET/PTC, and RAS mutations are associated with distinct microscopic, clinical, and biologic features of thyroid papillary carcinomas.     

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.     

Impact of pathognomonic genetic alterations on the prognosis of papillary thyroid carcinoma

Introduction  

BRAF mutations and RET or NTRK1 rearrangements were identified as causing events that drive the malignant transformation of the thyroid follicular cell. The impact of these alterations on the course of papillary thyroid carcinoma (PTC) is still unsettled.     

p14ARF、p53及脆性组氨酸三联体蛋白在甲状腺肿瘤中的表达

目的探讨p14ARF、p53及脆性组氨酸三联体(FHIT)蛋白在甲状腺肿瘤组织中的表达及其意义。方法采用免疫组织化学法检测20例甲状腺腺瘤和28例甲状腺癌组织(其中包括11例甲状腺滤泡癌(FTC)、12例乳头状癌(PTC)、4例髓样癌(MTC)以及1例未分化癌(UDTC)中p14ARF、p53及FHIT蛋白的表达。结果p14ARF、p53及FHIT蛋白在甲状腺腺瘤和甲状腺癌中阳性率分别为90%、36%;15%、75%;90%、7%,这3种蛋白在甲状腺腺瘤及甲状腺癌的表达差异均有统计学意义(P<0.05)。p14ARF、p53及FHIT蛋白的表达在FTC与腺瘤之间,PTC与腺瘤之间有统计学意义(P<0.05),p53及FHIT的表达在MTC与腺瘤间差异有统计学意义(P<0.05)。p14ARF、p53及FHIT蛋白的表达与甲状腺肿瘤的恶性进程有关,与患者年龄、性别以及淋巴结转移无关。另外p14ARF与FHIT蛋白的表达正相关,并且它们与p53均负相关。结论肿瘤抑制蛋白p14ARF和FHIT的缺失以及癌蛋白p53的高表达是甲状腺肿瘤发生的重要原因之一;联合检测p14ARF、p53及FHIT蛋白有助于区分甲状腺腺瘤和甲状腺滤泡癌。     

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。     

中国人甲状腺乳头状癌中RET基因重排及类型的分析研究

目的　建立检测RET基因重排的方法 ,研究中国人甲状腺乳头状癌 (PTC)中是否存在RET基因重排及其重排类型。方法　应用RT PCR方法对 110例PTC石蜡切片标本进行RET基因重排检测 ,并对扩增结果进行测序鉴定。结果　 76例PTC标本提取RNA成功 ,其中 60 .5 % (4 6/76)发生RET重排 ,13 .2 % (10 /4 6)表达PTC1,5 .3 % (4 /76)表达PTC3 ,2 .6% (2 /76)表达PTC4,其中PTC1发生的频率最高 ,实验中仅检测到 1例PTC2与PTC3 /PTC4混合型重排 ,可能中国人中PTC与RET和H4及ELE1重排激活有关。此外 ,还发现单一标本中有多种重排形式并存 ,比例高达 3 9.5 % (3 0 /76)。结论　中国人PTC组织中存在第 1、2、3、4种重排 ,且以第 1种较为常见。病例资料分析表明 :此多种重排混合的情形与肿瘤的大小、转移等无关。     

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。     

C MET蛋白在有颈部淋巴结转移的甲状腺癌中的表达和意义

目的探讨C-MET蛋白在有或无颈部淋巴结转移的甲状腺乳头状癌、甲状腺滤泡状癌及良性甲状腺组织中的表达及其临床意义。方法采用免疫组织化学方法检测有颈部淋巴结转移的甲状腺乳头状腺癌（PTC1组）62例，无颈部淋巴结转移的甲状腺乳头状腺癌（PTC2组）50例，甲状腺滤泡状腺癌（FTC组）l0例及良性甲状腺组织（良性组）30例中的C—MET蛋白的表达。结果PTCI组的C—MET表达明显高于其它3组（P〈0．001）。两两比较C—MET表达结果：PTC1组与PTC2组比较，P〈0．001；PTC1组与FTC组比较，P〈0．001；PTC1组与良性组比较，P〈0．001；PTC2组与FTC组比较，P=0．002；PTC2组与良性组比较，P〈0．001；皆有显著性差异。结论C—MET的表达是甲状腺乳头状癌是否有淋巴结转移的预测因子，是肿瘤的囊外扩展和直接侵犯的标记。该指标对甲状腺乳头状癌淋巴结转移的术前评估，决定手术方式均有一定指导意义。