Immunostaining for ret oncogene proteins in papillary thyroid carcinoma: a correlation of ret immunoreactivity and potential of lymph node metastasis.

Ret oncogenes, particularly Ret/PTC, have been associated with the potential of local invasion of papillary thyroid carcinoma (PTC). The purpose of this study was to investigate the correlation between the Ret oncogene expression and the potential of lymph node metastasis of PTC. A total of 107 PTC were microscopically reviewed to identify areas of infiltrating carcinoma (IC). IC was defined as tumor cells disposed in a haphazard pattern and in lobules, nests, follicles, or single cells within a desmoplastic or sclerotic stroma. All cases were submitted to immunostaining for Ret oncogene. There were 36 noninfiltrating PTC with lymph node metastasis in 1 case and 71 infiltrating PTC with lymph node metastasis in 40 cases. For non-PTC, the positive immunoreactivity was often weak to moderate and focal. For infiltrating PTC with IC, the IC displayed strong immunoreactivity. The noninfiltrating component of PTC with IC usually showed stronger reactivity than PTC without an infiltrating component. Furthermore, 36 of 40 metastatic PTC in lymph node were immunoreactive. Three follicular adenomas with areas of scar caused by fine-needle aspiration biopsy were not immunoreactive for Ret. In view of the high potential of infiltrating PTC for lymph node metastasis, distinction of this type of carcinoma from its noninfiltrating form is clinically important. Because immunoreactivity for Ret is usually positive in areas of infiltrating PTC and is often negative or focally positive in noninfiltrating PTC, immunostaining for Ret is helpful to identify infiltrating PTC and distinguish it from changes caused by fine-needle aspiration biopsy in benign thyroid lesions.     

Littoral cell angioma presenting as metastatic thyroid carcinoma to the spleen.

Papillary thyroid carcinoma (PTC) commonly metastasizes to cervical lymph nodes. Distant metastases are unusual with the lungs most frequently involved. Well-differentiated thyroid carcinoma very rarely presents with metastases to the spleen. This is the case of a 25-year-old man with a history of PTC (1.4 cm primary; no capsular invasion and negative lymph node metastases). One year after initial surgery, recurrent disease was found in multiple neck nodes by central neck dissection. Whole body scan (WBS) following a therapeutic ablation dose of 150 mCi I(131) revealed mediastinal metastases. Computerized axial tomography (CT) of the chest one year later showed no gross mediastinal or pulmonary disease. However, multiple large splenic lesions were incidentally noted. Evaluation by ultrasound (US) showed lesions to be solid echogenic masses without remarkable Doppler characteristics to suggest vascular tumors. US-guided percutaneous fine-needle aspiration biopsy (FNAB) of one lesion was nondiagnostic. After withdrawal from Levothyroxine, serum TSH was >100 mU/L with a thyroglobulin of 9.4 ng/mL and negative anti-thyroglobulin antibodies. Diagnostic WBS revealed faint splenic uptake but was otherwise unremarkable. Following treatment with 192 mCi I(131), WBS demonstrated increased activity in the mediastinum as well as in the spleen suggesting mediastinal and splenic metastases. Contrast CT of the abdomen showed multiple low-attenuated heterogeneously enhancing splenic masses, normal liver and no intra-abdominal lymphadenopathy. The largest mass (4.5 x 3.5 cm) was exophytic and in close proximity to the splenic capsule. Despite the serum thyroglobulin of only 9.4 ng/mL, the finding of I(131) accumulation within solid splenic masses led to a preoperative diagnosis of thyroid carcinoma metastases. To establish the diagnosis and to remove the risk for splenic rupture, a laparoscopic splenectomy was performed. Histopathologic analysis showed large littoral cell angiomas (LCA). False-positive radioiodine scintigraphy in the setting of PTC involving a vertebral hemangioma has been reported. To our knowledge, this is the first case that describes multiple angiomas mimicking metastatic thyroid carcinoma to the spleen. In one-third of all cases reported, LCA co-exists with various visceral organ cancers or malignant lymphoma. This is the first report of an association between LCA and thyroid carcinoma.     

Molecular analysis of multifocal papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) frequently presents as a multifocal process. To study the importance of separating independent primary (IP) from intrathyroid metastatic (ITM) PTC, we examined 19 molecular markers on 42 separate tumors from 18 multifocal PTC cases. In 12 of 18 (66.7%) cases, including 6 of 12 (50%) papillary microcarcinoma cases, the same or similar profile of loss of heterozygosities (LOH) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation was demonstrated, indicating that they were from the same primary and represented ITM. Different profiles of LOHs and BRAF mutation were detected in separate tumors of 6 of 18 cases, indicating that they represented IP. Patients with ITM, including papillary microcarcinoma, had significantly increased lymph node metastasis. The frequencies of LOHs of 17q21, 17p13, 10q23, and 22q13 were higher in tumors with lymph node metastasis, suggesting that these LOHs may be important in increased lymph node metastasis. LOH of 9p21 was found at the highest frequency in PTC (53.8%), followed by 1p36 (46.2%), 10q23 (34.6%), and 22q13 (34.6%). Papillary microcarcinoma had acquired similar genomic mutations as conventional PTC, but higher frequencies of mutations of BRAF, 1p36, 18q, and 22q13 were found in the larger PTC, suggesting that they might play a role in the aggressiveness of PTC. Different profiles of mutations were observed in conventional, follicular variants, and diffuse sclerosing variant of PTC, which might influence the different morphological appearances and clinical courses. In conclusion, molecular analysis can separate multifocal IP PTC from ITM PTC, and may be more important than tumor size in predicting lymph node metastasis, aggressiveness, and prognosis of PTC.     

TF-1细胞凋亡相关基因19与甲状腺肿瘤之间关系的初步探讨

目的 探讨TF-1细胞凋亡相关基因19(TFARl9)在甲状腺腺瘤(TA)和甲状腺乳头状癌(PTC)中是否有表达及其细胞定位。方法 6例TA和6例PTC患者,经手术得到甲状腺肿瘤组织标本并获病理诊断,以6例TA患者的瘤周正常甲状腺组织作为对照。TFAR19表达的检测采用免疫组化染色。结果 TFAR19在正常甲状腺组织中几乎未见表达;在TA组的甲状腺肿瘤组织中呈强阳性表达,而在PTC组中呈阴性表达。结论 TFAR19凋亡通路在TA中被激活,而在PTC中则受到抑制,提示细胞凋亡与增殖之间的平衡失调可能在PTC的发病机制中具有重要作用。     

RET activation and clinicopathologic features in poorly differentiated thyroid tumors.

Poorly differentiated carcinoma of the thyroid gland (PDC) represents an heterogeneous group of epithelial neoplasms with morphologic features and clinical characteristics intermediate between well differentiated and anaplastic (undifferentiated) carcinomas. Unlike well differentiated tumors, PDCs are associated with significant morbidity and mortality. The general prevalence of RET/PTC rearrangement in thyroid PDC and its impact on patient outcome are unknown. To address these issues and to identify prognostically relevant clinicopathologic parameters, we have investigated a series of 62 PDCs. RET/PTC rearrangement, analyzed by RT-PCR and immunohistochemistry using antibodies specific for the tyrosine kinase and juxtamembrane portions of the RET protein, was identified in 8/62 (12.9%) PDCs. RET/PTC was more common in cases with histologic evidence indicating coexistence with or possible evolution from a well differentiated papillary carcinoma (5 of 25 tumors, 20%) but did not correlate with other clinicopathologic parameters. The relatively low prevalence of RET activation in PDCs argues against a major role for RET/PTC in the progression from well to poorly differentiated thyroid tumor phenotypes. Survival analysis demonstrates that poor survival in PDC is associated with old age, male sex, invasion of extrathyroidal soft tissues, coexistence in the same tumor of oncocytic features with insular growth pattern, and distant metastases but not RET activation.     

Osteopontin is overexpressed in human papillary thyroid carcinomas and enhances thyroid carcinoma cell invasiveness

The transmembrane glycoprotein CD44v6 is overexpressed in most papillary thyroid carcinomas (PTC). We previously reported that osteopontin (OPN), a secreted glycoprotein that functions as a ligand for CD44v6, is overexpressed in thyrocytes transformed by the RET/PTC oncogene. OBJECTIVE: In this study we asked whether OPN is overexpressed in human PTC samples, and whether its expression correlates with clinical and histological features of the tumors. Furthermore, we wanted to establish the functional role of the CD44-OPN axis in thyroid tumorigenesis. DESIGN: Thyroid samples from 117 patients who had undergone surgical resection of the thyroid gland for benign or malignant lesions were collected. OPN and CD44 expressions were evaluated by immunohistochemistry with specific monoclonal antibodies. OPN expression was correlated with different PTC histological variants, lymph node metastasis, and PTC size. RESULTS: In this study we show that OPN is overexpressed in human PTCs with respect to normal thyroid tissue, follicular adenomas, and multinodular goiters (P < 0.05). The prevalence and intensity of OPN staining were significantly correlated with the presence of lymph node metastases (P = 0.0091) and tumor size (P = 0.0001). We also show that treatment of human PTC cells with recombinant exogenous OPN stimulated Matrigel invasion and activated the ERK and V-AKT murine thymoma viral oncogene homolog 1/protein kinase B; signaling pathways. Blockage of anti-CD44 antibodies prevented these effects. CONCLUSIONS: Given its prevalence and its correlation with aggressive features of human PTCs, we suggest that OPN might be used as a diagnostic and prognostic marker for these tumors. Furthermore, given the role of the OPN-CD44v6 axis in PTC cells, we suggest that CD44 and/or OPN may be molecular targets for therapeutic intervention in aggressive PTCs.     

Estrogen receptor (ER)-beta, but not ER-alpha, is present in thyroid vessels: immunohistochemical evaluations in multinodular goiter and papillary thyroid carcinoma.

OBJECTIVE: Estrogen receptors (ERs) have been demostrated in the vessel structures of several systems. Little is known on the presence of ERs in the thyroid vessels. DESIGN: We immunohistochemically evaluated both ER-alpha and ER-beta immunoreactivity (IR) in both vascular and follicular thyroid cells in tissue samples from 17 cases of multinodular goiter (MNG) and 17 cases of papillary thyroid carcinoma (PTC). MAIN OUTCOME: ER-alpha IR was undetectable in either tissue examined. In 100% of MNG samples, nuclear ER-beta IR was detected in both endothelial and follicular cells. In PTC samples, endothelial nuclear ER-beta IR was found in 100% of cases, whereas the nuclear staining of follicular cells was found in 83% of cases. The intensity of staining of the endothelial ER-beta IR was comparable between MNG and PTC. However, when follicular cells were considered, a tendency toward a decrease in nuclear staining and a significant increase in cytoplasmic staining were found in PTC lesions as compared to MNG. CONCLUSIONS: This study demonstrated that ER-beta, but not ER-alpha, IR is present in the endothelium of thyroid vessels. Furthermore, although data need to be confirmed in larger observations, these results suggest the lack of differences in the pattern of vascular ER-beta IR between MNG and PTC.     

桥本甲状腺炎不典型增生甲状腺上皮细胞的组织病理学研究

目的 探讨桥本甲状腺炎(HT)中不典型增生甲状腺上皮细胞(thyroid epithelial cells,TEC)的组织病理学改变及其与甲状腺乳头状癌(PTC)的关系.方法 从存档病例中选取30例HT不典型增生TEC病例和50例PTC,以甲状腺瘤旁滤泡和HT中的相对正常滤泡为对照组(各40例),进行常规形态学观察和细胞角蛋白19(CK19)、增殖细胞核抗原(PCNA)以及B细胞淋巴瘤因子2(Bcl-2)免疫组化标记(Max-Vision法),结果用x<'2>检验进行分析.结果 HT中不典型增生TEC有一定异型性,细胞排列拥挤,核增大,出现毛玻璃样改变.HT中不典型增生TEC和PTC上皮均明显表达CK19、PCNA和Bcl-2,与对照组相比差异有统计学意义(P<0.05),但前两组内差异无统计学意义(P>0.05).结论 HT中不典型增生TEC呈现某些PTC的形态学、免疫学表型特征,表达PTC特异的CK19,可能是HT癌变过程的中间环节,应引起高度重视.     

Failure to use measurement of megalin secretory components complexed with serum thyroglobulin as a tool to identify metastases after surgery in papillary thyroid cancer

When thyroid follicles are intact, some colloidal thyroglobulin (Tg) reaches the circulation by megalin-mediated transcytosis and is to various extents complexed with megalin secretory components. In contrast, in papillary thyroid cancer (PTC), serum Tg is not complexed with megalin because it is directly secreted by tumor cells. Here we attempted to use measurement of megalin secretory components to distinguish PTC patients with thyroid remnant plus metastases from those with thyroid remnant only, after thyroidectomy and before 131I ablation. Tg values in anti-Tg antibodies (TgAb)-free sera from 5 PTC patients with thyroid remnant plus metastases and 12 PTC patients with thyroid remnant only were measured following pre-adsorption with uncoupled protein A beads or with protein A beads coupled with antimegalin antibodies. The degree of Tg pre-adsorption with antimegalin antibodies was minimal, with no substantial differences between the two groups. Thus, we concluded that measurement of megalin secretory components is unlikely to be useful to identify the origin of serum Tg in PTC patients after thyroidectomy.     

Trend in thyroid carcinoma size, age at diagnosis, and histology in a retrospective study of 500 cases diagnosed over 20 years.

Recently, the Italian Network of Cancer Registries analyzed 5101 cases of thyroid carcinoma showing a reduction of mortality rate of 4%/year. This prompts us to evaluate the temporal trend in tumor size, age at diagnosis, and histology in a retrospective analysis of 500 thyroid cancers diagnosed over 20 years. Thyroid cancers were divided in two groups. The first included 193 cases diagnosed from 1985 to 1994, and the second 307 from 1995 to 2004. The size of all tumors was significantly reduced from 30 +/- 1.4mm in the first group to 15 +/- 0.8mm in the second group. In particular, papillary thyroid carcinoma (PTC) size decreased from 28 +/- 1.2mm to 14 +/- 0.8mm and follicular carcinoma from 40 +/- 6.3mm to 17 +/- 4.5 mm. Age at diagnosis of all carcinomas increased significantly from 40 +/- 1.3 years in the first group to 48 +/- 0.9 years in the second group. Analysis of the histological types revealed a significant increase of PTC rate in the second decade from 82% to 92% and a concomitant reduction of anaplastic thyroid carcinoma (ATC) from 3.7% to 1.0%. Moreover, a significant increase of micro-PTC rate, from 7.3% to 36.4%, was observed. In conclusion, it may be speculated that the above mentioned decreased mortality rate for thyroid carcinoma could be related to the significant reduction with time of cancer size, to the progressive increase of PTC rate and to the reduction of ATC rate. These data, if confirmed in other series, underscore the importance of evaluating thyroid nodules smaller than 10mm and corroborate recent findings suggesting that age be reconsidered as an independent prognostic factor for differentiated thyroid cancers.     

Incidence trends for papillary thyroid carcinoma and their correlation with thyroid surgery and thyroid fine-needle aspirate cytology.

CONTEXT: Papillary thyroid carcinoma (PTC) is the most prevalent endocrine malignancy. The reported incidence of PTC has more than doubled in many countries during the past half century. In Tasmania, an island state of the Commonwealth of Australia the incidence has increased by 24.7% per annum during the last two decades. OBJECTIVE: Using the Tasmanian population as a model, this study sought to determine the relationship between changes in PTC incidence and trends for utilization of thyroid surgery and thyroid fine-needle aspiration biopsy (FNAB) cytology. DESIGN: Hospital and pathology services in Tasmania provided data relating to all thyroid surgical, cytologic, and histopathology procedures undertaken between 1988 and 1998. The accuracy of PTC case ascertainment by the Tasmanian Cancer Registry was validated and the relationship between thyroid procedures and PTC incidence assessed. RESULTS: A total of 3452 individuals underwent a thyroid procedure, comprising 1968 surgical and 1756 FNAB cytologic procedures. Of these, 184 patients were diagnosed with thyroid carcinoma, of whom 121 (65.8%) had PTC. Thyroidectomy and thyroid FNAB increased by 7.0% and 49.7% per annum, respectively. The likelihood of diagnosing PTC in thyroidectomy specimens increased by 99.7% per year in those patients preoperatively assessed by FNAB, compared to 10.1% per year in those for whom a preoperative FNAB was not performed. PTC incidence increased independently of PTC tumor size, although the greatest increase occurred for PTC 1 cm or less with a history of preoperative FNAB. CONCLUSIONS: These results suggest increasing PTC incidence is largely attributable to greater diagnosis of small PTC, many of which are likely to have been asymptomatic, identified by neck ultrasonography and subsequent FNAB. However, the incidence of PTC larger than 1 cm in patients without history of preoperative FNAB has also risen, suggesting the occurrence of clinically relevant tumors may also have increased.     

乳头状甲状腺癌术后131I治疗后短期内TSH和甲状腺激素水平变化及临床意义

目的 探讨乳头状甲状腺癌(PTC)患者首次131I治疗清除残余甲状腺组织(清甲治疗)后第5天血清甲状腺功能指标的变化及临床意义.方法 PTC术后患者74例,首次131I清甲治疗剂量3.7 GBq,分别于131I治疗前1 d及治疗后第5天监测PTC患者血清FT3、FT4、TSH.以治疗前TSH水平分A、B两组:A组TSH＜30 mIU/L 22例,B组TSH≥30 mIU/L 52例.统计分析采用配对资料的符号秩和检验及相关性分析.结果 A组在131I治疗后第5天TSH下降87%,FT4升高88%,FT3升高87%,3项指标前后变化均有统计学意义(均P＜0.05),其中45%(10/22)患者达一过性甲状腺毒症水平.B组治疗后第5天三指标变化个体差异大,TSH小幅上升6%(P＞0.05);而FT4下降13%,FT3下降14%,前后变化有统计学差异(均P＜0.05).结论 针对PTC患者首次清甲治疗后短期内,部分患者甲状腺功能指标会升高甚至出现一过性甲状腺毒症,而另一些患者甲状腺激素只轻微下降,个体变化差异大.所以针对清甲治疗后的甲状腺激素替代和抑制治疗宜根据血清甲状腺功能指标监测结果制定个性化治疗计划.     

甲状腺乳头状癌患者ret基因重排突变

目的　研究ret基因重排突变与甲状腺乳头状癌(PTC)发生、发展的关系。方法　检测27例PTC,另有其他组织类型甲状腺癌10例、良性甲状腺病变33例及病变旁正常甲状腺组织30例(对照)甲状腺组织标本。首先以多重PCR筛查重排突变基因(ret/PTC)的存在,再以鉴定PCR(ID PCR)确定ret重排突变类型(ret/PTC1, 2, 3),最后通过自动测序证实。结果　(1)有15例标本显示ret/PTC阳性,其中11例为ret/PTC1; 3例为ret/PTC3; 1例为ret/PTC2。ID PCR产物通过直接基因测序得到证实。( 2 )所有15例ret/PTC阳性的组织标本均为PTC,发生率为55. 6% (15 /27)。(3)ret/PTC阳性及阴性的两组PTC患者在性别、年龄、肿瘤大小及颈部淋巴结累及率方面差异无统计学意义。但甲状腺外软组织侵犯率在ret/PTC阳性的患者低于阴性患者(33. 3% vs66. 7%,P<0. 05)。唯一1例有远处肺转移的患者为ret/PTC阴性。结论　ret重排突变特异性发生于PTC中,可能与PTC的发病密切相关。     

Intraocular and orbital metastasis as a rare form of clinical presentation of insular thyroid cancer

Insular carcinoma of thyroid is a rare tumor, which accounts for 4 to 6% of thyroid malignancies. Clinically and morphologically it is considered to be in an intermediate position between well-differentiated carcinoma of the thyroid (papillary or follicular) and undifferentiated or anaplastic carcinoma of the thyroid. Capsular and blood vessel invasion is seen frequently, and metastases to regional lymph nodes, lungs and bones are common. The initial presentation of distant metastasis in patients with thyroid cancer is rare. Thus metastatic thyroid carcinoma rarely involves the orbit. We report a rare case of choroidal metastasis from insular thyroid carcinoma.     

Thyrotoxicosis caused by thyroid cancer

Well-differentiated follicular carcinoma causing thyrotoxicosis is a rare entity. The age and sex distribution is no different from that of other patients with follicular carcinoma, with 87% older than the age of 40 and a female:male ratio of 3:1. The clinical presentation is similar to that of Graves' patients except that evidence of metastatic disease is often present (soft tissue masses, bone pain). The metastases are in the usual locations (bone, lung, mediastinum) and are often bulky. Despite the poor efficiency of iodine uptake and thyroid hormone production, the large tumor mass is capable of producing excessive hormone. Laboratory data confirm the hyperthyroid state, but the occurrence of T3 elevations with normal T4 levels is common, and T3 toxicosis may be missed if only T4 levels are measured. The role of thyroid stimulating immunoglobulins is still evolving, but such stimulators may support the growth of metastatic thyroid carcinoma and promote the development of hyperthyroidism. The treatment of these patients varied. Most had thyroidectomy followed by 131I therapy. Dosimetry allows for the administration of the largest dose of 131I with acceptable side effects. A good response to radioiodine predicted a more favorable outcome. The survival of patients with metastatic thyroid carcinoma causing hyperthyroidism does not differ from euthyroid patients with metastatic follicular disease (10-year survival, 59%).     

Relationship of sodium/iodide symporter expression with I131 whole body scan uptake between primary and metastatic lymph node papillary thyroid carcinomas

The aim of the present study was to evaluate total and membranous Na+/I- symporter (NIS) expressions in papillary thyroid carcinoma (PTC) tissue, correlation of NIS expression between primary and metastatic lymph node (LN) PTC tissues, and relationship of NIS expression with I131 whole body scan (WBS) uptake between primary and metastatic LN PTC tissues by analyzing 17 pairs of primary and metastatic LN PTC tissues. Staining positivity was calculated, and staining intensity was graded as negative (0), weak (1+), moderate (2+) and strong (3+). In primary PTC tissues, positivities and intensities of normal cells were higher than those of carcinoma cells but had no correlation with those in matched metastatic LN PTC tissues. In classic type, positivities, intensities and membranous intensities (mIS) were correlated between primary and matched metastatic LN PTC tissues. In patients aged younger than 45 yr, positivities and intensities in primary PTC tissues had correlation with those in matched metastatic LN PTC tissues. Positivities, intensities, mIS and pathological subtype of carcinoma cells in primary PTC tissues were not correlated with age, tumor size, TNM stage, MACIS score and thyroglobulin (Tg) levels at the time of I131 WBS. Sensitivity, specificity, as well as positive and negative predicted values of mIS in patients with I131 WBS uptake were 69.2, 75, 90 and 42.9% in primary PTC tissues, and 92.3, 100, 100 and 80% in metastatic LN PTC tissues. The results of mIS taken either as positive or negative were correlated with those of I131 WBS after controlling for age. Our results demonstrate that PTC tissues have altered total and membranous NIS expressions, suggesting that NIS expression in primary PTC tissues may predict NIS expression and I131 WBS uptake in matched metastatic LN PTC tissues.