Anaplastic Thyroid Carcinoma Survival

Anaplastic thyroid carcinoma is a rare, highly malignant tumor of elderly people. The purpose of this retrospective study was to characterize the patient population and to detect a potential subgroup with better prognosis or any intervention that would be useful. From 1967 through 1994 a total of 33 anaplastic thyroid carcinomas were operated on at the Second Department of Surgery, Helsinki University Central Hospital. There were 26 females and 7 males with mean age of 66.0 years (range 36–89 years). At the time of diagnosis 16 of 33 patients had distant metastases, and 32 of 33 of the tumors had invaded the thyroid capsule. Disease-specific survival was 9.7% (95% confidence interval from 2.0% to 25.9%) at 1 year using the product limit survival analysis. In the stepwise Cox proportional hazards regression model, local resectability (p= 0.0002), presence of distant metastases at diagnosis (p= 0.0014), radiotherapy (p= 0.014), and radioiodine ablation (p= 0.039) were independent prognostic factors. We concluded that even though statistically significant, independent, prognostic factors can be found the survival of the patients with the best prognostic characteristics is still poor. Only one patient, who had an anaplastic carcinoma focus within an encapsulated follicular thyroid carcinoma, survived in this series. At present there seems to be no surgical treatment that would be efficient for treating symptomatic anaplastic thyroid carcinoma.     

Prognostic Factors of Anaplastic Thyroid Carcinoma

Purpose. Anaplastic thyroid carcinoma (ATC) is a relatively rare but very aggressive malignancy, which usually results in death a few months after diagnosis. However, some patients survive for a long time, and the purpose of this study was to identify the prognostic factors of ATC.Methods. We retrospectively analyzed the records of 19 patients diagnosed with ATC in our institution between 1984 and 2002.Results. The median survival was 9.4 months, with a range of 0.6–76.3 months, and the 1-, 2-, and 5-year survival rates were 21%, 11%, and 5%, respectively. The mean tumor size was 5.7cm, with a range of 3.6–10.5cm, and complete resection was achieved in 4 patients. The prognostic factors according to univariate analysis were complete resection and small tumor size of less than 5cm (P = 0.005 and 0.047). However, according to multivariate analysis, complete resection was the only prognostic factor for ATC (P = 0.015). No association was found between survival and acute symptoms, chemotherapy, radiation therapy, extrathyroidal invasion, distant metastasis, age, or leukocytosis.Conclusion. At present, while there is no successful treatment regimen for ATC, only patients who undergo complete resection at a very early stage have any chance of long-term survival.     

Anaplastic Thyroid Carcinoma: A 25-year Single-Institution Experience

Background

Anaplastic thyroid carcinoma (ATC) is among the most aggressive solid tumors accounting for 1–5 % of primary thyroid malignancies. In this retrospective review, we aim to evaluate the prognostic factors, treatment approaches, and outcomes of patients with ATC treated at a single institution.

Materials and Methods

We retrospectively identified 95 patients with ATC from an institutional database between 1985 and 2010. A total of 83 patients with sufficient records were included in this study. Patient, tumor, and treatment characteristics were recorded. Disease-specific survival (DSS) was determined by the Kaplan–Meier method, and factors predictive of outcome were determined by univariate and multivariate analysis.

Results

Of the 83 patients, 41 were male and 42 were female. The median age at presentation was 60 years (range 28–89 years) with a median survival of 8 months. The 1- and 2-year DSS were 33 and 23 %, respectively. On univariate analysis, age less than 60 years, clinically N0 neck, absence of clinical extrathyroidal extension (cETE), gross total resection, and multimodality treatment were statistically significant predictors of improved survival. On multivariate analysis, absence of cETE, multimodality therapy, and gross total resection were predictors of improved outcome.

Conclusions

In patients with locoregional limited disease, multimodality treatment with gross total surgical resection and postoperative radiotherapy with or without chemotherapy offers the best local control and DSS.     

Anaplastic Carcinoma of the Thyroid Arising More Often from Follicular Carcinoma than Papillary Carcinoma

Background Anaplastic thyroid carcinoma (ATC), a rare and highly malignant tumor, has long been thought to arise from well-differentiated carcinoma (WDC) such as follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC). The purpose of this study was to test this notion by examining whether and, if so, how often ATC harbors the oncogenes that are commonly associated with WDC, such as RAS in FTC and BRAF in PTC. Methods We analyzed the mutation hotspots of BRAF (codon 600) and N-, K-, and H-RAS (codons 12, 13, and 61) in 16 ATCs. We also examined two genes, PIK3CA (exons 9 and 20) and TP53 (exons 5–9), both of which have been reported in ATCs. Results The results showed that approximately 31% (5 of 16) of ATCs harbored N-RAS mutation, 6% (1 of 16) had mutated BRAF, and approximately 56% (9 of 16) had mutated TP53. As to the three ATCs that had coexisted PTCs, mutated BRAF was detected in all PTC components but only in one ATC, while mutated PIK3CA was found in only one PTC component but not in the ATC. Conclusion A number of ATCs arise from WDCs, more often from RAS-mutant tumors than from BRAF-mutant tumors, implying that particular attention should be paid to the WDC harboring RAS mutation.     

Prognostic Factors and Therapeutic Strategy for Anaplastic Carcinoma of the Thyroid

Although anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, a few patients survive for a fairly long time after modern intensive treatment. We tried to identify prognostic factors of ATC to assist in deciding on the proper therapeutic strategy in individual patients. Of 47 patients with ATC (1976–1999), 3 patients with “incidental” ATC (largely differentiated thyroid carcinoma with a small region of ATC) were excluded because they had a favorable outcome. The 1-year survival rate of the remaining 44 patients with clinically distinct ATC was 16%. The presence of acute symptoms, large tumor (> 5 cm), distant metastasis, and leukocytosis (white blood cell count ≥ 10,000/mm³) proved to be significant risk factors. Multivariate analysis by the Cox proportional hazard model showed that these four factors were independent factors for predicting death from ATC. We devised a novel prognostic index (PI) based on the number of these four unfavorable characteristics the patient possessed. Patients with a PI of ≤1 had a 62% survival rate at 6 months, whereas no patients with a PI of ≥3 survived longer than 6 months. All patients with a PI of 4 died from their disease within 3 months. Nine patients received multimodal treatment with a combination of surgery, external irradiation, and chemotherapy and had a long survival (mean 333 ± 68 days; one patient is still alive and tumor-free), with a mean PI of 0.6. Our PI is useful as a means of selecting patients for aggressive therapy. When the PI is low, multimodal treatment should be attempted to obtain the best survival results; if it is high most patients are too seriously ill to tolerate intensive treatment and palliative therapy is recommended.     

Treatment Outcomes in Anaplastic Thyroid Carcinoma: Survival Improvement in Young Patients With Localized Disease Treated by Combination of Surgery and Radiotherapy

Background  Anaplastic thyroid carcinoma (ATC) is a notoriously aggressive malignancy associated with a highly lethal clinical course despite therapeutic intervention. Our present study attempts to identify factors that could potentially improve therapeutic strategies by analyzing the clinicopathological features, treatment and outcome of ATC patients managed over the past four decades at our institution. Methods  Fifty patients with biopsy-proven ATC during the period 1966 to 2006 were studied. All patients were managed with surgery, radiotherapy, chemotherapy and/or chemoradiation. Survival was calculated by the Kaplan-Meier method. Potential factors affecting survival were compared by the log rank test. Results  Most patients (88%) presented with a neck mass; 17 patients (34%) also had cervical lymphadenopathy. Distant metastases were clinically present in 9 (18%). Median survival was 97 days, whereas the 1- and 3-year survival was 14% and 8%, respectively. On univariate analysis, patients aged ≤65 years (P = .04), absence of metastatic disease at presentation (P < .01), surgical resection (P < .01), and postoperative radiotherapy (P < .01) were associated with longer survival. The adoption of cytotoxic chemotherapy was not associated with better survival (P = .4). Moreover, there was no improvement in survival rate over the last four decades despite the adoption of multimodal treatment (P = .5). Conclusion  ATC remains a deadly disease despite technical advances in surgical technique and adoption of multidisciplinary treatment strategies over the last four decades. However, younger patients with localized ATC might benefit from an aggressive multidisciplinary approach.     

Valproic Acid Sensitizes TRAIL-Resistant Anaplastic Thyroid Carcinoma Cells to Apoptotic Cell Death

Background

Anaplastic thyroid carcinoma (ATC) is an aggressive human tumor associated with a median survival of 2–6 months. TRAIL, as a ligand of death receptors, is known to induce apoptotic cell death in several cancer cells. However, TRAIL treatment alone is not effective against TRAIL-resistant cancer cells. This study was designed to investigate whether valproic acid (VPA) enhances apoptotic cell death of TRAIL-resistant ATC cells and to identify the mechanism of cell death of ATC cells by combination treatment with VPA and TRAIL.

Methods

To evaluate the cytotoxic effect of TRAIL and/or VPA on ATC cells, we used the MTT assay. The effects of VPA and TRAIL on apoptosis were assessed using FACS analysis (Annexin-V/PI stain) and Western blotting.

Results

The combination of VPA with TRAIL significantly induced apoptotic cell death compared with 8505C and ARO cells treated with TRAIL alone. The protein levels of cleaved caspase-8, -3, and PARP were increased in VPA and TRAIL co-treated ARO cells. The combination induced the activation of JNK and the phosphorylation of FADD and c-Jun but not p38. However, pretreatment with caspase inhibitors reduced the expression of cleaved caspase-8, -3, and PARP in co-treated ARO cells. SP600125 remarkably reduced the expression of cleaved caspase-8, -3, and PARP and the phosphorylation of FADD and c-Jun, as well as apoptotic cell death.

Conclusions

VPA sensitized TRAIL-resistant ATC cells to apoptotic cell death through involvement of the JNK pathway. Thus, the combination of VPA and TRAIL may be a promising therapy for ATC.

     

Prognostic Significance of Extrathyroid Extension of Papillary Thyroid Carcinoma: Massive but Not Minimal Extension Affects the Relapse-free Survival

Objectives Extrathyroid extension has been recognized as a prognostic factor in papillary thyroid carcinoma. In the most recent version of the UICC TNM classification system, extrathyroid extension has been classified into two grades, minimal extension (extension to sternothyroid muscle or perithyroid soft tissues) and massive extension (extension to subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve). In this study, we investigated the prognostic significance of each of the two types of extension. Patients and Methods One thousand and sixty-seven patients with papillary thyroid carcinoma without distant metastasis at surgery, who underwent surgical treatment in Kuma hospital between 1990 and 1995 and had been followed postoperatively for 60 months or more, were enrolled in this study. The grading of extrathyroid extension was based on both pathological findings and intraoperative surgical findings. Results In univariate analysis, although patients with massive extension showed a significantly worse relapse-free survival (RFS) rate than those with no or minimal extension (P < 0.0001), there was no difference in the RFS rate between patients with no extension and those with minimal extension. Among patients with massive extension, the RFS rate tended to be worse in those with posterior extension than in those with anterior extension (P = 0.0562). Furthermore, the RFS rate of patients with massive posterior extension only to the recurrent nerve demonstrated a better RFS rate than those with extension to other posterior organs (P = 0.0052). Multivariate analysis demonstrated that massive extrathyroid extension is recognized as an independent prognostic factor for RFS (P = 0.0003). Conclusions These findings suggest that (1) upgrading of T category for tumors with massive extension is appropriate, whereas that for tumors with only minimal extension is not, and (2) careful surgical treatment and postoperative follow-up are required for tumors with massive extension to posterior organs other than the recurrent laryngeal nerve.     

Anaplastic Thyroid Carcinoma Associated with Granulocyte Colony-Stimulating Factor: Report of a Case

A 75-year-old woman was hospitalized due to a right axillary mass. She had undergone a resection of thyroid carcinoma 13 years earlier, followed by two subsequent operations for recurrent thyroid disease. A physical examination revealed a right axillary mass associated with skin ulceration. Persistent bleeding was observed at the skin ulcer associated with the right axillary lymph node, despite conservative treatment for the lesion. Surgery was thus performed to control persistent bleeding from the axillary ulcer, and a histopathological examination resulted in a diagnosis of poorly differentiated thyroid carcinoma. The postoperative course was uneventful, but marked leukocytosis and extensive skin metastases were recognized 30 days postoperatively. A systemic examination revealed no other lesions associated with marked leukocytosis, but elevated levels of granulocyte colony-stimulating factor were noted in a blood examination. As a result, her general condition deteriorated rapidly and the patient died 2 weeks after the onset of leukocytosis.     

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.     

Impact of Lymph Node Ratio on Survival in Papillary Thyroid Cancer

Background

In papillary thyroid cancer, the role of lymph node dissection remains controversial, and staging systems consider metastatic lymph nodes as a binary entity. The purpose of this study was to determine a threshold lymph node ratio (LNR) that impacted disease-specific mortality (DSM).

Methods

We utilized the surveillance, epidemiology, and end results (SEER) database to analyze adult patients who underwent thyroidectomy with lymph node dissection. A LNR (metastatic lymph nodes to total lymph nodes) was calculated after eliminating patients with less than three nodes collected. Kaplan–Meier estimates for DSM were plotted for LNRs and compared by the log rank test. The Cox proportional hazards model was used to evaluate LNR with other known clinical and pathologic determinants of prognosis.

Results

A total of 10,955 cases contained data on lymph nodes. Median follow-up time was 25 months (range 0–59 months), and the mean LNR was 0.28 ± 0.37. After comparing Kaplan–Meier survival estimates and overall DSM rates, we found that a LNR ≥0.42 best divided those with lymph node metastasis based on DSM (p < 0.01). Those with a LNR ≥0.42 experienced a DSM rate of 1.72 % while those with a LNR <0.42 had a DSM rate of 0.65 % (p < 0.01). In addition, patients with a LNR ≥0.42 experienced a 77 % higher DSM rate compared to those with metastatic lymph nodes as a whole. When considered with other known determinants of prognosis, we found that LNR was strongly associated with DSM (hazard ratio 4.33, 95 % confidence interval 1.68–11.18, p < 0.01).

Conclusions

LNR is a strong determinant of DSM, and a threshold LNR of 0.42 can be used to risk-stratify patients with metastatic lymph nodes.     

Anaplastic Thyroid Carcinoma: Biology, Pathogenesis, Prognostic Factors, and Treatment Approaches

Background Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid tumors known to affect humans and carries a dismal prognosis. Our primary aim was to review its epidemiology, biology, risk factors, and prognostic indicators. We also reviewed the individual and combined roles of surgery, radiotherapy, chemotherapy, and newer therapeutic options in the management of ATC. Methods An extensive literature review was conducted to include all published reports on ATC. The changing trends in the management of anaplastic thyroid cancer were analyzed to summarize the current practice of management of ATC. Results Although ATC is rare, there has been a decline in its incidence worldwide. ATC accounts for more than half of the 1200 deaths per year attributed to thyroid cancer. Long-term survivors are rare, with >75% and 50% of patients harboring cervical nodal disease and metastatic disease, respectively, at presentation. ATC can arise de novo or from preexisting well-differentiated thyroid cancer. Surgical management has shifted from tracheostomy only for palliation to curative resection when possible. Tracheostomy is performed for impending obstruction rather than for prophylaxis. Radiotherapy has evolved from postoperative administration only to preoperative treatment, combining preoperative and postoperative treatment and using higher doses, along with hyperfractionating and accelerating dose schedules. Chemotherapy has changed from monotherapy to combination therapy, and newer drugs such as paclitaxel show promise. Similarly, novel angiogenesis-inhibiting agents are currently being used, with early reports of some benefit. Conclusions Despite multimodality approaches, ATC still carries a dismal prognosis. This should provoke innovative strategies beyond conventional methods to tackle this uniformly lethal disease.     

Encapsulated Anaplastic Thyroid Carcinoma Without Invasive Phenotype with Favorable Prognosis: Report of a Case

We herein report a case of anaplastic thyroid carcinoma in a 77-year-old woman with long-term disease-free survival. The tumor measured 7.5 × 6.0 cm in size and was diagnosed to be anaplastic carcinoma. We investigated the biological aggressiveness of this carcinoma by means of immunohistochemistry and found it have a high cell-proliferating activity, a disruption in the mechanism of apoptosis, and a high potential of cell spreading, similar to that observed in usual anaplastic carcinomas. The only unique point was that this tumor was encapsulated and no invasion of carcinoma cells beyond the capsule was microscopically observed. To avoid an obstruction of the trachea, a lobectomy without lymph node dissection was performed as a “palliative operation.” Although neither adjuvant chemotherapy nor radiotherapy was carried out due to her age, she has nevertheless survived with no evidence of recurrence for 57 months after surgery. The presence of such a type of anplastic carcinoma should thus be noted by surgeons and pathologists, even though the occurrence of such cases seems to be very rare. Received: November 28, 2001 / Accepted: July 2, 2002 Reprint requests to: Y. Ito     

Anaplastic Thyroid Carcinomas Incidentally Found on Postoperative Pathological Examination

Background

Anaplastic thyroid carcinoma (ATC) is occasionally found on postoperative pathological examination of patients with differentiated thyroid carcinoma (DTC). There is no general consensus on how we should treat these incidentally diagnosed ATC (incidental ATC).

Materials and methods

A total of 675 patients with ATC were registered with the ATC Research Consortium of Japan. These patients were treated between 1995 and 2008 in 38 registered institutions. About 81 % of the ATC patients had common-type ATC and about 14 % had ATC co-existing with a metastatic DTC lesion. The remaining 5 % had incidental ATC. Among the patients with incidental ATC, we investigated 25 patients whose clinical data were fully available. We examined the clinical profile of incidental ATC, and the relationships between treatment and outcome in patients with incidental ATC.

Results

The tumor size was clearly smaller, and patients with extrathyroid invasion or distant metastasis were significantly fewer in incidental ATC than in common-type ATC. Most incidental ATC coexisted with papillary carcinoma. While the clinical course of incidental ATC was favorable compared with common-type ATC, half of the patients had disease-related deaths. The prognostic factors of incidental ATC were nearly the same as those of common-type ATC, but the tumor size alone was an independent factor on multivariate analysis. Regarding treatments, the outcome was more favorable in those who underwent curative resection, and the clinical course showed a slight improvement by the addition of external beam radiotherapy and/or chemotherapy after curative resection, but it did not reach statistical significance.

Conclusion

Incidental ATC is the only curable type of ATC, and further studies are needed to establish the effectiveness of additional postoperative radiotherapy and/or chemotherapy in incidental ATC.     

Anaplastic Thyroid Carcinoma: Expression Profile of Targets for Therapy Offers New Insights for Disease Treatment

Background Anaplastic thyroid cancer is an endocrine malignancy. Its rare and rapidly lethal disease course has made it challenging to study. Little is known regarding the expression by anaplastic tumors of molecular targets for new human anticancer agents that have been studied in the preclinical or clinical setting. The objective of this work was to evaluate the expression profile of anaplastic thyroid tumors for molecular targets for treatment. Methods Of the 94 cases of anaplastic thyroid cancers diagnosed and treated in British Columbia, Canada over a 20-year period (1984–2004), 32 cases (34%) had adequate archival tissue available for evaluation. A tissue microarray was constructed from these anaplastic thyroid tumors and immunohistochemistry was utilized to evaluate expression of 31 molecular markers. The markers evaluated were: epidermal growth factor receptor (EGFR), HER2, HER3, HER4, ER, PR, uPA-R, clusterin, E-cadherin, β-catenin, AMF-R, c-kit, VEGF, ILK, aurora A, aurora B, aurora C, RET, CA-IX, IGF1-R, p53, MDM2, p21, Bcl-2, cyclin D1, cyclin E, p27, calcitonin, MIB-1, TTF-1, and thyroglobulin. Results A single tumor with strong calcitonin expression was identified as a poorly differentiated medullary carcinoma and excluded from the study cohort. The mean age of the anaplastic cohort was 66 years; 16 patients (51%) were females, and the median patient survival was 23 weeks. A wide range in molecular marker expression was observed by the anaplastic thyroid cancer tumors (0–100%). The therapeutic targets most frequently and most strongly overexpressed by the anaplastic tumors were: β-catenin (41%), aurora A (41%), cyclin E (67%), cyclin D1 (77%), and EGFR (84%). Conclusions Anaplastic thyroid tumors exhibit considerable derangement of their cell cycle and multiple signal transduction pathways that leads to uncontrolled cellular proliferation and the development of genomic instability. This report is the first to comprehensively evaluate a panel of molecular targets for therapy of anaplastic thyroid cancer and supports the development of clinical trials with agents such as cetuximab, small-molecule tyrosine kinase inhibitors, and aurora kinase inhibitors, which may offer new hope for individuals diagnosed with this fatal thyroid malignancy.