The likely transformation of papillary thyroid carcinoma into anaplastic carcinoma during postoperative radioactive iodine-131 therapy: Report of a case

We report herein a case of papillary carcinoma which appeared to transform into anaplastic carcinoma during postoperative radioactive iodine-131 (¹³¹I) therapy. A 67-year-old man who was diagnosed as having papillary thyroid carcinoma with bilateral neck lymph node involvement and multiple lung metastases underwent total thyroidectomy prior to ¹³¹I therapy. Immediately after a second course of ¹³¹I therapy, the patient complained of right neck pain and swelling, and a biopsy of the swollen neck lymph node was taken. Histologic examination of this biopsy specimen revealed anaplastic carcinoma. With p53 immunohistochemical staining, both the primary tumor and the biopsy specimen were positive. We speculate that first, some DNA damage in tumor cells was induced by the initial ¹³¹I therapy, but neither DNA repair nor cell apoptosis occurred because the p53 gene was already mutated; then further DNA damage was induced by the second ¹³¹I therapy, leading to anaplastic transformation. Received: September 3, 1999 / Accepted: May 30, 2000     

手霉素通过反应性氧基诱导甲状腺未分化癌KAT-4细胞凋亡

目的研究手霉素对甲状腺未分化癌KAT-4细胞的作用,探讨其作用机制。方法使用人的甲状腺未分化癌KAT-4细胞,MTT细胞毒性测定评价手霉素对KAT-4细胞的作用,使用annexin v和一氧化氮(nitric oxide,NO)染料标记细胞,应用流式细胞仪术检测细胞内NO生成和细胞凋亡;细胞内超氧阴离子通过二氢乙啶(dihydroethidium,DHE)测定;采用荧光法测定谷胱甘肽(glutathione,GSH)。结果手霉素降低KAT-4细胞活性,且呈剂量依赖性。手霉素诱导KAT-4细胞凋亡和反应性氧基(reactive oxygen species,ROS)产生包括NO和超氧阴离子增加和GSH降低。手霉素诱导细胞凋亡与ROS的增加有关,N-乙酰基-L-半胱氨酸(N-acetyl-L-cysteine,NAC)可抑制ROS产生,保护KAT-4细胞逃避手霉素的细胞毒作用和避免手霉素诱导的凋亡。结论细胞内ROS的产生对手霉素的细胞毒作用起非常重要的作用。手霉素通过增加ROS产生诱导甲状腺癌细胞凋亡。     

Pretherapeutic drug evaluation by tumor xenografting in anaplastic thyroid cancer

Background

Despite various attempts at modifying usual treatment modalities, anaplastic thyroid cancer (ATC) is still associated with unfavorable prognosis. Results of preclinical investigations are often of limited transferability to clinical tumor biology. Individualized multimodal treatment regimens, including novel growth-inhibiting drugs, might be a future option.

Methods

Tumor tissue, freshly prepared from a patient operated for ATC, was xenotransplanted to nude mice. While the patient obtained a hyperfractionated external beam radiation, mice carrying xenotransplanted tumors were randomized (n = 6) and treated by multikinase inhibitors (sorafenib [S]: vascular endothelial growth factor receptor [VEGF-R], platelet derived growth factor receptor, RET; vandetanib [V]: VEGF-R, endothelial growth factor receptor [EGF-R]; and MLN8054 [M]: Aurora kinases [AK]). Antiproliferative, antiangiogenic, and proapoptotic effects were evaluated.

Results

Treatment of successfully xenotransplanted fresh ATC tumor tissue by multikinase inhibitors and aurora kinase inhibitor reduced the tumor volume up to 61% depending on the drug and time of application (3 wk of treatment: 46% [M], 34% [V], 30% [S]; 5 wk of treatment: 61% [S]). Tumor cell proliferation (BrdU) was reduced between 34% and 58% [S] and [V]. Reduction of tumor vascularity was between 67% [V] and 33% [S] and was accompanied by decreased EGF-R/VEGF-R2 receptor activity [V/V,S]. Tumor cell apoptosis (caspase 3 activity) increased up to 2.4-fold [S].

Conclusions

Successful in vivo evaluation of novel drugs in xenotransplanted fresh tumor tissue allows in-time (while patient receives standard treatment) prospective analysis for possible additional clinical application. However, technical specifications have to be taken into account to obtain stable in vivo tumor growth. Based on the individual results, a tailored clinical drug application seems possible.     

The effect of surgery and radiotherapy on outcome of anaplastic thyroid carcinoma

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is an aggressive rare tumor. We analyzed our experience for prognosis and the effect of surgery and radiotherapy on patients with ATC. METHODS: We conducted a retrospective review of all patients (n = 67) with ATC treated at a tertiary care center from 1969 to 1999. Survivor median follow-up was 51 months. Tumor and patient characteristics and therapy were assessed for effect on survival by multivariate analysis. RESULTS: Patients presented with a neck mass (99%), change of voice (51%), dysphagia (33%), and dyspnea (28%). Surgery was performed in 44 of 67 patients, with 12 complete resections. The 6-month and 1- and 3-year survival rates were 92%, 92%, and 83% after complete resection; 53%, 35%, and 0% after debulking; and 22%, 4%, and 0% after no resection, respectively (P < .0001). A radiation dose of >45 Gy improved survival as compared with a lower dose (P = .02). Multivariate analysis showed that age < or = 70 years, absence of dyspnea or dysphagia at presentation, a tumor size < or = 5 cm, and any surgical resection improved survival (P < .05). CONCLUSIONS: Candidates for surgery with curative intent for ATC are patients < or = 70 years, tumors < or = 5 cm, and no distant disease. Radiotherapy >45 Gy improves outcome.     

Immunophenotyping of thyroid tumors identifies molecular markers altered during transformation of differentiated into anaplastic carcinoma

Background

The objective of this study was to evaluate the change in the tumor expression profile that occurs during the transformation of differentiated thyroid cancer (DTC) into anaplastic thyroid cancer (ATC) and to evaluate an 8-marker transformation panel previously identified through evaluation of ATCs and their adjacent associated DTCs.

Methods

Tissue microarrays were constructed from 19 ATCs and 96 DTCs (90 papillary carcinomas and 6 follicular carcinomas), and immunohistochemistry was used to evaluate the expression of 54 molecular markers. Significant associations between marker staining and cancer pathology (DTC vs ATC) were determined using contingency table and marginal homogeneity tests. A Random Forests classifier algorithm was also used to identify useful or important molecular classifiers.

Results

Overall, there were 25 significantly differentially expressed markers when comparing ATCs with DTCs. These included 5 of the 8 markers that were previously identified as being altered during anaplastic transformation and 3 additional markers were also found to be highly significantly differentially expressed by ATCs and DTCs. Clustering and classification analysis based on the previously identified 8-marker transformation panel, or the 5 of these markers that were found to be most important in the current study, readily separated DTC and ATC with a high degree of accuracy.

Conclusions

The markers observed to change during thyroid cancer progression validate prior observations and represent promising molecular diagnostic or prognostic tools and identify targets for therapy of ATC.     

甲状腺未分化癌的综合治疗

甲状腺未分化癌是临床少见而发展快速的高度恶性肿瘤。调强放疗有利于局部病灶的控制,改善病人的生存质量。多个肿瘤中心在探索手术、放疗、化疗的综合治疗。     

Papillary Thyroid Carcinoma: Factors Influencing Recurrence and Survival

Background The prognosis of patients with papillary thyroid carcinoma (PTC) is usually favorable; however, a subset of patients can develop local recurrence or distant metastases. The aim of this study was to evaluate the prognostic factors influencing the recurrence and the survival rate in 950 PTC patients. Materials and Methods From 1990 to 2005, 950 consecutive patients affected by PTC were operated on at our Department. We analyzed the prognostic role of the following parameters: gender, age at initial treatment, extent of thyroid surgery, node dissection, tumor size, node metastases, distant metastases, stage, and 131-I therapy. Results Seventy-nine patients (8.3%) developed locoregional or distant metastases after an average follow-up of 7.8 years (range 2–17 years); in particular local recurrence was observed in 25 cases and distant metastases in 54 cases. The global 10- and 15-year survival rates were 91.38% and 88.69%, respectively. At univariate analysis, all variables were significantly correlated with recurrence (P = .001) except gender (P = .3); moreover, gender (P = .2), node dissection (P = .5), and node metastases (P = .06) were not significant on 10- and 15-year survival. At multivariate analysis the age at first treatment, T4, M+, stage IV, the extent of thyroid surgery, and the 131-I therapy resulted to be significant and independent prognostic factors (P < .001). Conclusion Our data, in disagreement with other staging systems, suggest that gender does not play a significant role both in recurrence and survival. Moreover, the 131-I therapy was a statistically significant prognostic factor at univariate and multivariate analyses.     

结节性甲状腺肿合并甲状腺癌的诊断和治疗

目的：总结结节性甲状腺肿并存甲状腺癌的诊断和治疗的经验。 方法：回顾性分析2007年1月—2012年12月手术治疗并经病理证实的185例结节性甲状腺肿并存甲状腺癌患者的临床资料。 结果：同期手术治疗的结节性甲状腺肿患者共1 657例,185例（11.16%）合并甲状腺癌,其中乳头状癌158例（85.4%）,滤泡状癌17例（9.2%）,混合型癌9例（4.9%）,未分化癌1例（0.5%）。结节性甲状腺肿合并甲状腺癌患者钙化发生率（42.8%,74/173）明显高于单纯结节性甲状腺肿患者（10.8%,159/1472）（χ2=130.16,P=0.00）;砂砾钙化患者癌变率（100%,36/36）明显高于非砂砾样钙化者（19.3%,38/197）（χ2=91.49,P=0.00）。患者均行术中快速病理检查（除12例近期外院已确诊）,并根据不同情况均采取了不同范围的手术方式,术后均终生服用甲状腺素片。 结论：结节性甲状腺肿并存甲状腺癌时,多为分化好的乳头状癌。对于合并钙化,特别是砂砾样钙化的结节性甲状腺肿应积极手术治疗。结节性甲状腺肿的手术中应行快速病理检查帮助诊断,从而有利于术中选择正确的手术方式。     

结节性甲状腺肿与甲状腺癌关系的探讨

目的探讨结节性甲状腺肿与甲状腺癌之间的关系。方法对 5 0 8例结节性甲状腺肿 ,5 2例甲状腺癌的病理特点、癌前病变、二者之间的过渡及癌旁病变 ,进行分析研究。结果结节性甲状腺肿伴非典型增生为 6 .9% (35 / 5 0 8) ,其中轻度非典型增生占 6 .1% (31/ 5 0 8) ,重度非典型增生占 0 .8% (4 / 5 0 8)。结节性甲状腺肿伴癌变为 1.2 % (6 / 5 0 8)。甲状腺癌旁伴有结节性甲状腺肿病变者达 81% (4 2 / 5 2 )。结论结节性甲状腺肿是甲状腺癌的癌前疾病 ,其发生发展过程中可发生癌前病变 ,对伴有非典型性增生的病例应加强随访。     

Prognostic relevance of previous exposure to ionizing radiation in well-differentiated thyroid cancer

Background and aims Although exposure to ionizing radiation is a well-known risk factor for well-differentiated thyroid cancer, its effects on tumor behavior remain unclear. This study was undertaken to address this question.Materials and methods We randomly selected 426 patients who underwent thyroidectomy for cancer between 1964 and 2000 and divided them into two groups: previously exposed (ExR); not exposed to radiation (nExR). Data were retrospectively collected.Results There were 340 female patients and 86 male, age 9–89 years with mean follow-up of 56 months. The ExR group (n=68) was smaller than the nExR group (n=358). Most patients in the ExR group (64.5%) had previously received therapeutic radiation, whereas 25% were occupationally exposed and 10.5% were at risk from environmental radiation. Both groups were similar with regard to extent of thyroidectomy and adjuvant treatment, but neck dissections were more frequent in the nExR group. There were no significant differences between both groups for age, gender, tumor multicentricity, frequency of microcarcinoma, histology, lymph node disease, distant metastasis, and local recurrence. Incidental microcarcinomas were more frequent in the ExR (35.3%) group than in the nExR group (22.1%). Mean tumor size in the ExR group (18.7 mm) was smaller than in the nExR group (22.3 mm).Conclusion Ionizing radiation increases risk for well-differentiated thyroid cancer (WDTC) but not adverse cancer behavior. Surgeons should be aware of the high incidence of microcancer among patients with previous exposure to radiation.Poster presentation at the Annual Meeting of The American Head & Neck Society, 11–13 May 2002, Boca Raton, Florida, USA     

结节性甲状腺肿合并甲状腺癌的诊治分析

目的提高结节性甲状腺肿合并甲状腺癌的诊断和治疗水平。方法回顾性分析我院近年收治的158例结节性甲状腺肿患者的临床资料,所有患者均首先采用单侧或双侧甲状腺次全切除术,术中送冰冻病理检查,根据冰冻病理结果或石蜡切片病理结果补充行患侧甲状腺叶全切＋峡部＋对侧甲状腺叶次全切除术。结果158例结节性甲状腺肿患者中,合并甲状腺癌23例,其中乳头状腺癌22例,滤泡状腺癌1例。术后随访5-12个月,1例患者出现颈部淋巴结肿大,再次行功能性颈部淋巴结清扫术。Logistic回归分析显示,判断结节性甲状腺肿合并甲状腺癌的因素中,结节个数较少与结节直径较小是结节性甲状腺肿合并甲状腺癌的危险因素。结论对某些虽然无明确症状,但发现甲状腺有较小的实性结节的结节性甲状腺肿患者应持更积极的治疗态度。     

Time interval in diagnosis and treatment of papillary thyroid cancer: a descriptive, retrospective study

Background

Studies have investigated delays in the diagnosis of neoplasms to identify delays to treatment on the part of patients and primary care practitioners. The aim of the current study was to evaluate the time interval (TI) required for the diagnosis of symptomatic papillary thyroid carcinoma (PTC).

Methods

The study included 97 patients with PTC. Other histologic types and incidental microcarcinomas were excluded. The primary outcome variable was the TI between the occurrence of a sign/symptom and thyroidectomy. TI was composed of: patient's TI (PTI), diagnostic TI (DTI), and therapeutic TI (TTI).

Results

The TI between the occurrence of a sign/symptom and thyroidectomy averaged 3 months. PTI ranged from 25-85 days, DTI from 12-40 days, and TTI from 7-30 days. PTI was higher (P < .05) than DTI and TTI.

Conclusion

PTI is the most important factor affecting TI. Implementation of information may increase patient's alertness and reduce misinterpretation of signs/symptoms. Collaboration between specialists is fundamental to further reduce DTI and TTI.     

Prognostic factors for survival in pancreatic cancer: a population-based study

BACKGROUND: We performed a population-based study of patients from the deep South of the United States (with >25% black residents) to evaluate the survival rate of patients with pancreatic cancer. Our aims were to analyze prognostic factors influencing pancreatic cancer survival using the population-based Alabama Statewide Cancer Registry and to determine whether race/ethnicity is an independent determinant of outcomes in patients with pancreatic cancer. METHODS: Eligible participants included all persons diagnosed with pancreatic cancer from 1996 to 2000 and reported to the Alabama Statewide Cancer Registry. Survival time was calculated from time of diagnosis to death for pancreatic cancer deaths or to date of last contact or death from other causes for censored participants. Risk factors associated with survival were assessed with the Kaplan-Meier survival method and the log-rank test. Demographic, tumor, and treatment variables were assessed using the Cox proportional hazards model. RESULTS: Of 2230 patients, the median age at diagnosis was 71 years and the male to female ratio was approximately 1:1. Seventy-three percent of patients were white, and 27% of patients were black. The distribution by stage was 12.5% localized disease, 29.6% regional, 35.3% distant, and 22.6% unstaged. The median survival time for all patients was .39+/-.01 years. Patients who underwent surgical treatment were less likely to die of pancreatic cancer (hazard ratio, .48; 95% confidence interval, .41-.56). Similarly, patients who underwent either chemotherapy or radiation therapy had improved survival rates (hazard ratio, .62; 95% confidence interval, .53-.73). Across all stages, black patients were significantly less likely to receive chemotherapy compared with white patients (26.7% vs 32.3%, P=.02), and were less likely to receive surgical intervention (14.02% vs 17.0%, P=.09). When examining patients who were offered their therapy of choice but refused, we found across all stages that a greater proportion of black patients refused therapies versus whites: 5.6% versus 2.9% (P=.02) for chemotherapy, 3.8% versus 1.6% (P=.04) for radiation, and 9.0% versus 3.3% (P=.001 for surgery). The Cox proportional hazard model showed no effect of race on overall survival time while controlling for stage at presentation, type of therapy received, age at diagnosis, and site of primary tumor. CONCLUSIONS: Survival in patients with pancreatic cancer remains dismal. Tumor characteristics and treatment factors are related directly to survival time in patients with pancreatic cancer. Black patients were less likely to receive therapy but also were more likely to refuse the indicated therapy. Factors leading to racial disparity in the treatment of pancreatic cancer warrant further investigation.