Poorly differentiated and anaplastic thyroid carcinomas: chromosomal and oligo-array profile of five new cell lines

Information on gene alterations associated to poorly differentiated (PDTC) and anaplastic thyroid carcinomas (ATC) is scarce. Using human cancer cell lines as a tool for gene discovery, we performed a cytogenetic and oligo-array analysis in five new cell lines derived from two PDTC and three ATC. In PDTC we evidenced, as important, the involvement of the MAPK/ERK kinase pathway, and downregulation of a group of suppressor genes that include E-cadherin. In ATC, downregulation of a specific group of oncosuppressor genes was also observed. Our ATC cell lines presented chromosomal markers of gene amplification, and we were able to identify for the first time the nature of the involved amplicon target genes. We found that the main molecular differences between the two cell line types were related to signal transduction pathways, cell adhesion and motility process. TaqMan experiments performed for five amplicon target genes and for two genes, which allowed a clear distinction between ATC and PDTC: CDH13 and PLAU corroborated array results, not only in the cell lines, but also in an additional set of primary 14 PDTC and three ATC. We suggest that our findings may represent new tools for the development of more effective therapies to the hitherto untreatable ATC.     

Poorly differentiated (anaplastic) seminoma of the testis

Anaplastic seminoma constitutes approximately 17% of total experience with seminoma at Memorial Sloan-Kettering Cancer Center. Among 25 previously untreated patients, 11 (44%) were clinical Stage I, and 14 (56%) were clinical Stage II or III. Treatment of these 25 patients with the same regimens employed for classical seminoma yielded an overall 80% 5-year apparent cure rate. Survival rates were poor in eight previously treated patients referred with recurrence.     

Malignant transformation of thyroid cancer; poorly differentiated cancer and anaplastic cancer transformation

The prognosis of thyroid cancer depends largely on histological differentiation and clinical stage. The prognosis in anaplastic cancer is worst, in well differentiated cancer it is best; poorly differentiated cancer takes a middle position. The prognosis of patients with differentiated cancer is generally good, however, there are cases with malignant transformation such as poorly differentiated, anaplastic and squamous-cell cancer transformation. We studied the frequency and the inducement factors of malignant transformation in patients with thyroid cancer. The frequency of poorly differentiated, anaplastic and squamous-cell cancer transformation was 13.6%, 6.4% and 0.7%, respectively. In anaplastic cancer transformation, irradiation is an important factor.     

Fatal differentiated thyroid cancer

Thirty-five patients who died of differentiated thyroid cancer were analyzed for factors affecting survival. The neck was the most common initial site of recurrence (62.0%). The lung was the most common metastatic site (56.7%). Major sites associated with death were locoregional recurrence (neck and mediastinum: 48.6%) and bone metastases (22.9%). By univariate analysis, local tumor extension, type of initial surgery, and residual tumor and/or existence of distant metastases at the initial operation were significant factors affecting survival. Stepwise multivariate analysis revealed that invasion of the esophagus and/or carotid artery shortened survival and that multiple surgeries extended survival. Our results suggest that to improve survival in patients with differentiated thyroid cancer, better locoregional control, including multiple surgical resection, is necessary. © 1996 Wiley-Liss, Inc.     

Aggressive differentiated thyroid cancer

Differentiated thyroid cancer is characteristically associated with an innocuous clinical course, but a minority of cases may manifest surprisingly aggressive behaviour. Such aggressive DTC are directly responsible for the majority of thyroid cancer related deaths. Moreover, they contribute indirectly to increased DTC-related morbidity, because our inability to differentiate these tumours from innocuous DTC at an early stage fuels a significant degree of DTC overtreatment around the globe. In the present paper we describe how improved understanding of the clinicopathological thyroid tumour progression model and optimization of clinical staging systems continues to improve our ability to diagnose and treat aggressive DTC. Early recognition of aggressive DTC allows instillation of an aggressive management strategy which is based upon surgical-oncologic completeness, and minimization of treatment-related sequelae through continued development of reconstructive options and focussed delivery of adjuvant treatments.     

Well differentiated thyroid cancer

Cancers of follicular cell origin are the most common of the endocrine malignancies. Thyroid cancers are seen with increased frequency after radiation exposure and in some familial syndromes. Interestingly, the prognosis of thyroid carcinoma is highly dependent on the age of the patient at the time of examination: several clinical staging systems facilitate appropriate treatment planning. The ability of the follicular cell to take up iodine permits the use of radioactive iodine for follow-up and therapy. After thyroidectomy and radioiodine ablation, thyroglobulin becomes a sensitive marker for the presence of recurrent or metastatic disease. Patients who are thyroglobulin-positive but radioiodine-negative or who have antithyroglobulin antibodies are a clinical challenge. Improvement in imaging studies can help in the treatment of these patients. New treatments, such as the use of agents to improve iodine uptake in follicular cell tumors, are in early clinical investigation; others are in experimental development but hold promise for the treatment of aggressive thyroid malignancies.     

Poorly differentiated carcinoma and germ cell tumors.

Although many questions remain unanswered, recent clinical and pathologic studies have shed considerable light on the subject of carcinoma of unknown primary site. It is now clear that some patients in this group have extragonadal germ cell tumors. This is suggested by the superior treatment results in patients with clinical features of extragonadal germ cell tumor and is confirmed by the finding of the diagnostic chromosome abnormality in tumor cells of some patients. These patients have tumors that are unrecognizable using all available pathologic techniques other than molecular genetic analysis; most patients also do not have elevated serum tumor marker levels. Young men with poorly differentiated carcinoma located predominantly in the mediastinum or retroperitoneum should be strongly suspected of having germ cell tumors; chromosomal analysis should be obtained if possible, and these patients should be treated as for germ cell tumor. It is clear that some responsive patients with poorly differentiated carcinoma do not have extragonadal germ cell tumors. A few patients initially thought to have poorly differentiated carcinoma actually have non-Hodgkin's lymphoma. With the widespread availability of immunoperoxidase staining for LCA, this diagnostic error should be minimized. Other responsive patients have poorly differentiated neuroendocrine tumors. The nature and spectrum of neuroendocrine tumors is still being defined; however, our initial documentation of cisplatin responsiveness has been confirmed, even in poorly differentiated neuroendocrine tumors with a known primary site. It is likely that additional responsive subgroups also exist but have not yet been identified. With the availability of a diagnostic chromosomal marker, the answers to other questions regarding the relationship of poorly differentiated carcinoma and germ cell tumors will soon be forthcoming.(ABSTRACT TRUNCATED AT 250 WORDS)     

甲状腺低分化滤泡状癌30例临床分析

背景与目的：甲状腺低分化滤泡状癌较少见,但有其一定的临床特征和发展规律。本研究探讨其临床特征、治疗效果及预后,旨在提高对本病的认识。方法：回顾分析30例低分化滤泡状癌的临床资料。用Kaplan-Meier法统计生存率,用log-rank检验模型对患者年龄、性别、肿瘤大小、外侵程度、治疗方式和手术切除程度等可能的预后因素进行分析,用t检验分析两组数据之间是否有显著性差异。结果：3、5和10年的总生存率分别为32．2％、25．1％和12．5％;3、5年累积肿瘤复发率分别为37．6％和48．0％。3、5年颈淋巴结转移率为57．6％、68．2％,3、5年远处转移率为82．5％和86．9％。根治性切除原发灶及颈部转移灶可显著降低肿瘤复发(χ^2=6．59,P=0．01),改善生存率(χ^2=12．40,P=0．00)。伴有静脉瘤栓的肿瘤复发率明显高于其他患者(χ^2=4．62,P=0．03)。接受I治疗的远处转移患者的生存时间显著长于未行I治疗的患者(χ^2=12．25,P=0．00)。结论:甲状腺低分化滤泡状癌的远处转移率高,预后差,远处转移是影响预后的主要原因。手术切除是提高局部控制和改善预后的关键,I治疗远处转移有效,可延长生存时间。     

甲状腺未分化癌的研究进展

甲状腺未分化癌（anaplastic thyroid cancer,ATC）是一种罕见的甲状腺肿瘤,约占甲状腺恶性肿瘤的1%~2%,是最具侵袭性的甲状腺癌,可导致显著的发病率和死亡率。高龄、男性、双侧肿瘤、局部浸润和（或）远处转移等是多数ATC患者预后欠佳因素。ATC最佳治疗方案尚未明确,目前虽以手术、放疗、化疗、靶向治疗、免疫治疗等综合治疗为主,然而治疗现状不容乐观。本文通过整理国内外ATC的相关研究,就目前的诊断、治疗方案、近期临床试验结果,以及今后的研究方向等进行综述,为ATC的诊疗决策提供参考。      

超声对低分化和未分化甲状腺癌的诊断价值

目的 探讨超声对低分化甲状腺癌(PDTC)和未分化(间变性)甲状腺癌(UTC)的诊断价值.方法 应用彩色多普勒超声对22例PDTC和UTC的甲状腺形态、大小、回声、边界、内部砂粒、血流分布等声像图表现及其内部血流状况进行观察,并与手术、活组织病理检查病理结果对照;扫查颈部及气管食管沟区淋巴结.根据甲状腺双叶或单叶弥漫性病变及局部淋巴结的超声表现,结合临床表现,判断甲状腺病变的性质.结果 术前或活组织病理检查前超声检出甲状腺单叶肿物16例,左甲9例,右甲7例.双叶肿物6例.超声提示UTC 2例,甲状旁腺癌1例,慢性淋巴细胞性甲状腺炎1例,其余提示甲状腺恶性肿瘤.结论 超声检查可提高PDTC和UTC的检出率和诊断率.     

Multimodal approach to anaplastic thyroid cancer

Despite more than 50 years of research, the overall clinical outcomes of patients afflicted with anaplastic thyroid cancer remain dismal. Survival is limited by the dire consequences of an uncontrolled primary and the prevalence of overt or occult distant metastasis. Local control is influenced by multiple confounding variables, including the inherent biological aggressiveness of the disease and the seemingly insurmountable technical obstacles to both surgery and radiotherapy. In response to these challenges, revolutionary changes in the treatment paradigm over the last 20 years, specifically the adoption of a multimodal treatment strategy, suggest improvements in local control and short-term median survival and have changed the pattern of progression, even for patients presenting with locally advanced disease. For the first time there is attestation of even long-term survivorship for a few patients who harbor advanced local, but nonmetastatic, disease. The current challenge is to address the high incidence of apparent or occult distant metastasis. Newly developed targeted therapies are likely to change the treatment paradigm, and they hold the promise of being able eventually to make treatment with curative intent available to some patients.     

Hexokinase isoenzymes from anaplastic and differentiated medullary thyroid carcinoma in the rat

The activity, isoenzyme distribution and compartmentation of hexokinase (ADP: d-hexose-6-phosphotransferase, EC 2.7.1.1) were compared in slowly growing, well-differentiated medullary thyroid carcinoma (DMTC) and rapidly proliferating anaplastic thyroid carcinoma (AMTC) in the rat. Individual isoenzymes from either soluble or particulate fractions after solubilization were obtained by fast protein liquid chromatography and were kinetically analyzed either in soluble form or after (re)binding to rat liver mitochondria. These studies were undertaken to test the hypothesis that the growth rate of tumors is correlated with the activity of mitochondrial-bound hexokinase in our tumor system. In contradiction to this hypothesis, we found no difference in either enzyme activity or compartmentation of both kinds of tumors. The major part of enzyme activity was soluble (73 and 78% in DMTC and AMTC respectively). In addition, no major differences were observed in the kinetic properties of the individual isoenzymes of both tumors. Only soluble type II hexokinase from AMTC had a slightly decreased apparent K_m for glucose. There appeared to be some differences in isoenzyme composition: both tumors contained type I and type II hexokinase in the soluble as well as in the particulate fractions. However, the proportion was shifted in favor of type II hexokinase in the soluble fraction of AMTC. Additional findings of this study were the following: the affinity of type II hexokinase to both substrates glucose and MgATP²⁻ was significantly less compared to type I hexokinase. However, the inhibition constant for glucose-1,6-diphosphate of both isoenzymes was exactly the same. The bound form of both isoenzymes had the same substrate affinities as the soluble form but was considerably less inhibited by glucose-1,6-diphosphate. In the latter respect, type I and type II hexokinase behaved in the same way.     

Risk factor analysis in differentiated thyroid cancer.

Six hundred patients with primary differentiated thyroid carcinoma had follow-up studies for a minimum of 15 years and a maximum of 45 years. Recurrence rate and death rate were significantly different in defined high-risk and low-risk groups of patients. These basic risk groups were defined by age and sex alone; low risk consisted of men 40 years of age and younger and women 50 years of age and younger whereas the high-risk group were older patients. Recurrence and death rates in patients at high risk were 33% and 27% while respective figures for patients at low risk were 11% and 4%. In more recent years these results have shown significant improvement. Basic risk group definition outweighed the effect of pathologic type, local disease extension, type of treatment, and site of recurrence or metastasis. For instance, radioactive iodine cured 70% of patients at low risk with metastatic disease but only 10% of patients at high risk. Less aggressive biologic behavior of thyroid cancer before the age of menopause implies that an estrogen-rich milieu may alter the effects of initiating and promoting factors in carcinogenesis. It also suggests that therapeutic trials of estrogen be undertaken in progressive metastatic differentiated thyroid cancer.     

Co-existent anaplastic and well differentiated thyroid carcinomas: a nuclear DNA study

Clonal transformation of well differentiated follicular or papillary carcinomas has been suggested as a mechanism by which anaplastic carcinomas of the thyroid might arise. Of 126 cases of anaplastic (giant cell) carcinomas, 17 (13.5%) contained histologically well differentiated tumour foci within or adjacent to the high grade malignant anaplastic tumour. Cytophotometric DNA analysis after Feulgen staining was performed on 11 cases in order to evaluate ploidy of the anaplastic and the well differentiated tumour cells. The majority of these co-existent carcinomas (9/11) were papillary. All 11 anaplastic carcinomas demonstrated an aneuploid DNA pattern which correlated with a poor clinical outcome (7 of 11 died of disease in less than 6 months). In contrast six co-existent papillary and one co-existent follicular tumours were diploid. These data show that the co-existence of anaplastic and well differentiated carcinoma occurs only rarely and when it occurs only one third of the well differentiated tumours contain aneuploid tumour cells. This suggests that in the majority of cases of anaplastic thyroid carcinoma the malignant cells arise de novo rather than through clonal transformation of well differentiated carcinomas.     

Locally advanced differentiated thyroid cancer

Although most patients with differentiated thyroid cancer (DTC) of follicular cell origin enjoy a relatively good prognosis, some patients unfortunately present with or develop locally advanced DTC which leads to significant local morbidity and mortality. DTC accounts for 54-94% of all locally advanced thyroid cancers. DTC invasion of the recurrent laryngeal nerve, strap muscles and trachea are the most common followed by invasion of the esophagus, internal jugular vein and carotid artery. Surgical resection is the primary treatment for locally advanced DTC. Although the optimal surgical approach (ranging from conservative shave excision to aggressive en bloc resection of tumor and vital structures) in patients with locally advanced DTC is controversial, a curative resection should be the goal unless complete tumor resection results in unwanted perioperative morbidity and mortality or widely metastatic disease is present. Postoperative radioiodine ablation with TSH suppression is imperative after surgical resection of locally advanced DTC. Patients with microscopic or small gross residual disease, after surgical resection, may benefit from postoperative external radiotherapy for local control of disease.     

Poorly differentiated medullary carcinoma of the stomach.

BACKGROUND. The biologic behavior of poorly differentiated medullary carcinoma of the stomach is unclear. METHODS. A clinicopathologic study on 74 poorly differentiated medullary carcinomas (PMC) and 73 nonmedullary carcinomas (NMC) of the stomach was done. PMC were defined as gastric carcinomas in which more than 50% of the tumor area contained poorly differentiated adenocarcinoma with no fibrous stroma. RESULTS. They were characterized by a location in the upper 33% of the stomach (49%), grossly expansive growth (69%), frequent vascular permeation (57%), and simultaneous liver metastasis (15%). Although the 5-year survival rate was similar for PMC and NMC, death of PMC was related more frequently to liver metastasis (47%) and less frequently to peritoneal dissemination (12%). The outcome of patients with PMC was influenced by frequent vascular permeation, extended lymph node metastasis, and simultaneous liver metastasis. CONCLUSIONS. These results indicate that PMC are characterized by expansive growth of the tumor and simultaneous or recurrent metastasis to the liver. Therefore, the biologic behavior of poorly differentiated medullary carcinoma is similar to that of well-differentiated carcinoma of the stomach.     

Evaluation of Aurora kinase inhibition as a new therapeutic strategy in anaplastic and poorly differentiated follicular thyroid cancer

Due to an unfavorable prognosis using the usual therapy, patients with anaplastic thyroid cancer (ATC) are in desperate need of new therapeutic strategies. The objective of this study was to evaluate the effects of MLN8054, an inhibitor of the Aurora serine/threonine kinases, on ATC cells in vitro and on ATC xenografts as a new therapeutic strategy for ATC. Three anaplastic (Hth74, C643, Kat4) and one follicular (FTC133) thyroid cancer cell lines were evaluated in vitro and Kat4 xenografts in vivo. The antiproliferative effect of MLN8054 (0.1-10 μM) on thyroid cancer cells was quantified by sulphorhodamine B-assay. The proapoptotic effect and the effects on the cell cycle were evaluated by flow cytometry after Annexin-V-FITC staining. Further Histone H3 phosphorylation was analysed. In vivo, antiproliferative and antiangiogenic effects were assessed by tumor volume and morphometric analysis following immunohistochemical staining (Ki-67, pHisH3, CD31). Treatment of the different TC cells with MLN8054 inhibited proliferation in a time- and dose-dependent manner, with IC(50) values between 0.1 and 10 μM. Administration of MLN8054 resulted in an increase of apoptotic cells, decreased Histone H3 phosphorylation and induced cell cycle arrest. In vivo, treatment of ATC by MLN8054 resulted in an up to 86% reduced tumor volume and 89% reduced tumor vascularity. In conclusion, our data demonstrated that Aurora kinase inhibition is effective in reducing cell growth and inducing apoptosis of ATC in vitro and tumor growth and vascularity in vivo. Controlled clinical studies on MLN8054 or comparable compounds would be worthwhile to evaluate its potential therapeutic value for treatment of ATC.