Mitsuji Nagahama

Prognostic Factors and Treatment Outcomes of 100 Cases of Anaplastic Thyroid Carcinoma

BACKGROUND Anaplastic thyroid carcinoma (ATC) is a malignancy with one of the highest fatality rates. Here we report a retrospective study of the treatment and other factors associated with its outcomes. MATERIALS AND METHODS The medical records of 100 patients diagnosed with ATC at Ito Hospital between 1993 and 2009 were reviewed and pertinent information was extracted and analyzed. RESULTS There were 80 women and 20 men, and their median age at diagnosis was 68 years (range, 41-90 years). Thirteen patients had a history of well-differentiated thyroid carcinoma. Six patients had a small ATC focus within a differentiated carcinoma. All cases were retrospectively staged according to the Union for International Cancer Control classification system, and the results were stage IVA in 11 cases, stage IVB in 31 cases, and stage IVC in 58 cases. Seventy patients underwent surgical treatment, and complete resection was performed in 24 of them. Seventy-eight patients received radiotherapy, and 58 of them received a total dose of ≥40 Gy. Twenty-seven patients received chemotherapy. Only 15 patients received multimodal therapy (surgery, radiotherapy, and chemotherapy). The 1-year survival rates according to stage were as follows: stage IVA, 72.7%; stage IVB, 24.8%; and stage IVC, 8.2%. Multivariate analysis identified age ≥70 years, white blood cell ≥10,000 mm(3), extrathyroidal invasion, and distant metastasis at the time of diagnosis as prognostic factors. Survival after complete resection was significantly better than after incomplete resection or no resection. The results also suggested that radiation doses of ≥40 Gy were associated with significantly longer survival. CONCLUSION Although the prognosis of most patients with ATC continues to be poor, surgery, radiotherapy, and a combination of both improved the survival of patients with ATC.

Clinical evaluation of color Doppler imaging for the differential diagnosis of thyroid follicular lesions

Ultrasonography (US) of the thyroid gland has recently proved to be a useful clinical diagnostic method, and the newly developed high-resolution US with a color Doppler flow mapping function can reveal fine details of the thyroid gland and the hemodynamic features of a thyroid neoplasm. US can yield a diagnostic accuracy of more than 90% for thyroid carcinoma, especially papillary carcinoma. However, neither conventional B-mode US imaging nor aspiration biopsy cytology has delivered satisfactory results for follicular carcinoma. The aim of this study was to evaluate the clinical usefulness of color Doppler imaging for the differential diagnosis of thyroid follicular lesions. A color Doppler scan was performed in 310 patients with a solitary cold nodule, and a combination of B-mode US and color Doppler findings, including tumor vascularity and results of a fast Fourier transform (FFT) analysis were used to create the following diagnostic grading system for differential diagnosis of follicular lesions: grade 1, benign follicular lesion [no color flow mapping (CFM) inside the nodule]; grade 2, benign peripheral type [CFM only in peripheral area, pulsatility index (PI) < 1.0]; grade 3, suspected follicular carcinoma (penetrating CFM, vascularity moderate); grade 4, follicular carcinoma (high-velocity penetrating CFM, PI = 1.0). All patients were subjected to surgical resection, and histologic examination was used to confirm the diagnosis. The grades of the177 adenomatous nodules were as follows: grade 1, 46.9%; grade 2, 48.0%; grade 3, 5.1%; grade 4, 0%. The corresponding percentages for the 89 follicular adenomas were 16.9%, 49.4%, 30.3%, and 3.4%; and for the 44 follicular carcinomas they were 0%, 13.6%, 45.5%, and 40.9%. On the assumption that grade 1 and 2 lesions are benign and grade 3 and 4 lesions are malignant, 38 of the 44 follicular carcinomas and 227 of the 266 benign tumors had been accurately diagnosed, yielding a sensitivity of 88.9%, a specificity of 74.2%, and an accuracy of 81.0% for the grading system. Color Doppler imaging of 310 follicular tumors has revealed that high-velocity pulsatile blood flow penetrating the tumor is a characteristic finding of follicular carcinoma and is a new diagnostic criterion for performing color Doppler imaging. The differential diagnostic grading scores for color Doppler examinations and the results of FFT analysis demonstrate that US with the color Doppler function can play an important role in the differential diagnosis of thyroid tumors.

Outcomes and Prognostic Factors of 251 Patients with Minimally Invasive Follicular Thyroid Carcinoma

BACKGROUND Radioiodine ablation after total thyroidectomy is the generally accepted treatment for patients with widely invasive follicular thyroid carcinoma (FTC). The therapeutic strategy for minimally invasive FTC, on the other hand, is still a matter of controversy. The histological diagnosis of minimally invasive FTC is often made after lobectomy. The aim of this study was to determine the factors associated with the development of distant metastases in patients with minimally invasive FTC. METHODS Between 1989 and 2006, 251 patients with minimally invasive FTC underwent initial surgery at our hospital. Their median follow-up period was 7.2 years. There were 194 women and 57 men. Their mean age at the time of surgery was 46 years. Distant metastases were diagnosed in 54 patients (21.5%). In 22 of them distant metastases were diagnosed at the time of the initial surgery (M1), and in the other 32 they were diagnosed during the follow-up period. Age at initial surgery, sex, primary tumor size, histological findings (differentiation, and extent of vascular and capsular invasion), completion total thyroidectomy, and distant metastases at initial surgery were assessed as prognostic factors for distant-metastases-free survival (DMFS) and cause-specific survival (CSS). The Kaplan-Meier method and log-rank test were used to analyze time-dependent variables. The Cox proportional hazard model was used to perform the multivariate analysis. RESULTS Univariate analysis showed that age (45 years or older) and primary tumor size (4 cm or more) were significant prognostic factors related to postoperative distant metastases in the group of 229 patients without distant metastases at time of the initial surgery. The cumulative survival rate was significantly poorer in M1 patients, patients aged 45 years or older, and patients whose primary tumor size was 4 cm or more. Multivariate analysis showed that age was a significant prognostic factor both for DMFS and CSS. CONCLUSIONS Age was the most powerful prognostic factor for patients with minimally invasive follicular thyroid cancer. The prognoses of patients younger than 45 years old were excellent and distant metastases rarely occurred. Routine completion total thyroidectomy and radioiodine ablation is thought unnecessary for these patients.

Prognosis and Prognostic Factors for Distant Metastases and Tumor Mortality in Follicular Thyroid Carcinoma

BACKGROUND Distant metastases are more common in patients with follicular thyroid carcinoma (FTC) than in patients with papillary thyroid carcinoma, and the outcome is often poorer in patients with distant metastases. In this study, we attempted to identify the risk factors for distant metastases in FTC. METHODS Between 1989 and 1997, 134 patients with FTC underwent initial surgery, and their median follow-up period was 12.5 years. Seventeen patients had widely invasive FTC, and 117 had minimally invasive FTC. Distant metastases were observed in 36 patients (26.9%). Thirteen of these patients had distant metastases at the time of initial surgery (M1), and in the other 23 patients distant metastases were diagnosed with during their follow-up periods. Risk factors for distant metastases and cause-specific survival were analyzed. The factors analyzed were age at the time of initial surgery, sex, primary tumor size, histological findings (invasiveness, extent of vascular, and capsular invasion), and distant metastases at the time of initial surgery. RESULTS Univariate analysis showed that age and primary tumor size were significant factors related to postoperative distant metastases in the group of 121 patients who did not have distant metastases at the time of initial surgery. When the patients with M1 were included, the cumulative distant metastases-free-survival rate was significantly lower in the group with widely invasive FTC. The cumulative survival rate was significantly higher in the groups of patients with the minimally invasive type, who were under 45 years old, whose primary tumor size was under 4 cm and who did not have distant metastases at the time of the initial surgery. Multivariate analyses showed that tumor size and age were significant risk factors for postoperative distant metastases and that age and the presence of distant metastases at the time of the initial surgery were significant risk factors for poorer cause-specific survival. CONCLUSION Age and primary tumor size were significant risk factors for postoperative distant metastases. Based on the findings in this study, we conclude that conservative management is sufficient for younger patients with minimally invasive FTC whose primary tumor is small.

Up-regulation of transcriptional factor E2F1 in papillary and anaplastic thyroid cancers

AbstractExpression of genes in the Rb-E2F signaling pathway is controlled by E2F transcriptional factors originally defined as molecules that bind to the promoter of E2 adenovirus. The E2F gene family consists of six members and is designated E2F1-6. The Rb-E2F signaling pathway is among the main regulators of the cell cycle, hence its importance in differentiation and oncogenesis. We document here up-regulation of E2F1, but not other members of the E2F gene family, in 15 of 18 primary papillary thyroid cancers examined (83%) in comparison to corresponding noncancerous thyroid tissues and in all of 11 anaplastic thyroid cancer (ATC) cell lines (100%). The E2F4gene, however, was down-regulated in 12 of the papillary thyroid cancers (67%). Immunohistochemical analysis with antibody to E2F1 revealed prominent intracellular E2F1 protein in most of the primary papillary cancers (16 of 18; 89%) but was not detectable in normal thyroid tissues. These data indicated that increased expression of the E2F1 gene might play a significant role in human thyroid carcinogenesis through derangement of the Rb-E2F signaling pathway.

Overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) as a novel gene responsible for anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma (ATC) is one of the most fulminant human malignancies. However, the molecular carcinogenic mechanisms of ATC are understood poorly. Recently, the authors performed a cyclic DNA (cDNA) microarray analysis with 11 anaplastic thyroid carcinoma cell lines (ACLs) and discovered several novel responsible genes for ACLs and ATC. From the extended list, they focused on hypothetical and anonymous genes and investigated a novel gene, named the overexpressed in anaplastic thyroid carcinoma‐1 (OEATC‐1) gene.

Pediatric differentiated thyroid carcinoma in stage I: risk factor analysis for disease free survival

BackgroundTo examine the outcomes and risk factors in pediatric differentiated thyroid carcinoma (DTC) patients who were defined as TNM stage I because some patients develop disease recurrence but treatment strategy for such stage I pediatric patients is still controversial.MethodsWe reviewed 57 consecutive TNM stage I patients (15 years or less) with DTC (46 papillary and 11 follicular) who underwent initial treatment at Ito Hospital between 1962 and 2004 (7 males and 50 females; mean age: 13.1 years; mean follow-up: 17.4 years). Clinicopathological results were evaluated in all patients. Multivariate analysis was performed to reveal the risk factors for disease-free survival (DFS) in these 57 patients.ResultsExtrathyroid extension and clinical lymphadenopathy at diagnosis were found in 7 and 12 patients, respectively. Subtotal/total thyroidectomy was performed in 23 patients, modified neck dissection in 38, and radioactive iodine therapy in 10. Pathological node metastasis was confirmed in 37 patients (64.9%). Fifteen patients (26.3%) exhibited local recurrence and 3 of them also developed metachronous lung metastasis. Ten of these 15 achieved disease-free after further treatments and no patients died of disease. In multivariate analysis, male gender (p = 0.017), advanced tumor (T3, 4a) stage (p = 0.029), and clinical lymphadenopathy (p = 0.006) were risk factors for DFS in stage I pediatric patients.ConclusionMale gender, tumor stage, and lymphadenopathy are risk factors for DFS in stage I pediatric DTC patients. Aggressive treatment (total thyroidectomy, node dissection, and RI therapy) is considered appropriate for patients with risk factors, whereas conservative or stepwise approach may be acceptable for other patients.

Clinicopathological study of clear-cell tumors of the thyroid: An evaluation of 22 cases

Twenty-two cases of partial or wholly composed clear-cell thyroid tumors were reviewed to differentiate between a primary nodule and metastatic clear-cell renal carcinoma in the thyroid. Pathological reevaluation of HE-stained specimens, immunohistochemical observation using anti-thyroglobulin (TG) antibody, and periodic acid-Schiff (PAS) staining were performed. The pathological characteristics in metastases from the kidney have a greater tendency to demonstrate a strikingly clear cytoplasm with small nuclei, rich vascularization, and a trabecular arrangement of tumor cells than do primary thyroid cases. The immunohistochemical TG staining in conjunction with PAS staining for the recognition of follicular colloid could provide much more reliable information of primary cases compared to that using TG staining alone. Clinically, in primary cases, the female: male ratio is substantially higher while the mean age is lower than in metastatic cases reflecting differentiated thyroid carcinoma. In conclusion, immunohistochemical staining for TG with PAS staining for the recognition of follicular colloid proved to be the most sensitive method for identifying primary clear cell thyroid tumors. In addition, a careful assessment of past and/or present kidney disorders to rule out metastatic renal cell carcinoma is advisable. Age, gender, and physiological findings are also informative when differentiating between them.

Does Completion Thyroidectomy Improve the Outcome of Patients with Minimally Invasive Follicular Carcinoma of the Thyroid

AbstractBackground The diagnosis of minimally invasive follicular thyroid carcinoma (MIFTC) is often made histologically after thyroid lobectomy. We attempted to determine whether completion thyroidectomy should be considered necessary for all patients diagnosed with MIFTC after thyroid lobectomy.MethodsThe subjects of this study were a total of 324 patients who underwent thyroid lobectomy as initial surgery at our institution between 1989 and 2010 and diagnosed histologically as MIFTC. Completion thyroidectomy was performed on 101 patients, and the other 223 patients were followed up without further treatments. Cumulative cause-specific survival (CSS) rates and distant-metastasis-free survival (DMFS) rates were calculated by the Kaplan–Meier method. Differences between groups were analyzed for statistical significance by the log-rank test. Multivariate analysis was performed by using the Cox proportional hazards model.ResultsDuring the follow-up period, 39 patients were diagnosed with distant metastasis, and 7 patients died of their disease. Age at the initial surgery was found to be a significant factor related to DMFS in both the univariate and multivariate analysis and to also be related to CSS in the univariate analysis. Completion thyroidectomy did not have a significant effect on DMFS or CSS according to the results of the univariate analysis, but it had significant effect on DMFS according to the results of the multivariate analysis.ConclusionsAlthough we were unable to demonstrate sufficient statistical evidence that completion thyroidectomy improved the outcome of MIFTC patients, it is noteworthy none of the patient who underwent completion thyroidectomy died of the disease.

Long-term changes in parathyroid function after subtotal thyroidectomy for graves' disease.

BackgroundTransient hypocalcemia is one of the postoperative complications of thyroidectomy for Graves’ disease, and perioperative parathyroid hormone (PTH) assays are used to predict postoperative hypocalcemia. We evaluated long-term changes in parathyroid function after surgery for Graves’ disease.MethodsSerum PTH values were measured in Graves’ patients with postoperative hypocalcemia, and those patients were followed postoperatively.ResultsSubtotal thyroidectomy was performed in 275 patients with Graves’ disease. Their serum calcium levels were measured on postoperative day (POD) 1, and patients with transient postoperative hypocalcemia were treated with calcium and vitamin D supplementation and followed up. The amount of calcium and vitamin D supplementation was adjusted to keep the patient’s serum calcium level within the normal range. Measurement of their serum intact PTH value on POD 1 revealed normal value in 18 patients, a below normal level in 22, and an above normal level in the other 2. During the follow-up period, the serum iPTH values remained normal in 12 patients, recovered to the normal level in 21 patients, and rose above the normal range in 9 patients. The serum iPTH values of all patients eventually reached the normal range during the follow-up period. A marked difference in preoperative serum alkaline phosphatase concentration was observed between the high-iPTH patients and the normocalcemic patients.ConclusionsThe phenomenon of an elevated serum PTH level after surgery for Graves’ disease was observed in 21% of the patients with postoperative hypocalcemia despite the achievement of normal serum calcium levels by calcium and vitamin D supplementation.