Takuya Higashiyama

Risk Factors for Recurrence to the Lymph Node in Papillary Thyroid Carcinoma Patients without Preoperatively Detectable Lateral Node Metastasis: Validity of Prophylactic Modified Radical Neck Dissection

BackgroundAlthough papillary carcinoma usually shows mild characteristics, it metastasizes and shows recurrence to the lymph node in high incidences. Of the two representative lymph node compartments to which papillary carcinoma metastasizes, the central compartment can be routinely dissected via the surgical incision made for thyroidectomy. However, the routine application of prophylactic lateral node dissection (modified radical neck dissection [MND]) remains controversial. In this study, we investigated risk factors for lymph node recurrence of papillary carcinoma to determine the appropriate application of prophylactic MND.MethodsWe investigated risk factors for lymph node recurrence in 1,231 patients without preoperatively detectable lateral node metastasis who underwent thyroidectomy, central node dissection, and prophylactic MND for papillary carcinoma between 1987 and 1995.ResultsThe incidence of lateral node metastasis and the number of metastatic lateral nodes significantly increased with carcinoma size. The lymph node disease-free survival (LN-DFS) was also significantly worse in carcinoma with a maximal diameter greater than 3 cm. Massive extrathyroid extension, male gender, and age 55 years or older also reflected a poorer LN-DFS. The 10-year LN-DFS rates of patients with carcinoma having two and three or four of these features were low at 88.5% and 64.7%, respectively, although the rates of those with carcinoma having no or only one characteristic were better than 95%.ConclusionsProphylactic MND is recommended for cases of papillary carcinoma demonstrating two or more of the following four characteristics; male gender, age 55 years or older, maximal tumor diameter larger than 3 cm, and massive extrathyroid extension.

Clinical Significance of Lymph Node Metastasis of Thyroid Papillary Carcinoma Located in One Lobe

BackgroundPrevious studies have shown that lymph node metastasis can be of prognostic value. In this study, we investigated the clinical significance of node metastasis focusing on metastasis in the central compartment for patients with papillary carcinoma located in one lobe.Patients and MethodsWe investigated the frequency of lymph node metastasis in 759 patients with papillary carcinoma to determine whether and how such metastasis affects disease-free survival (DFS).ResultsCentral node metastasis was observed in 63% of patients, and the frequency was increased in relation to tumor size. The frequency of lateral node metastasis was 62.0%, which was also directly related to tumor size. On multivariate analysis of cases showing tumor larger than 1 cm, central node metastasis was recognized as an independent prognostic factor of DFS. The frequency of metastasis to the paratracheal nodes contralateral to the tumor was drastically elevated for tumors larger than 1 cm, but metastasis to this region did not independently predict worse DFS.ConclusionCentral node metastasis independently predicts a worse DFS for patients with papillary carcinoma larger than 1 cm.

Prognostic Impact of Serum Thyroglobulin Doubling-Time Under Thyrotropin Suppression in Patients with Papillary Thyroid Carcinoma Who Underwent Total Thyroidectomy

BACKGROUND Detectable serum thyroglobulin (Tg) in patients with papillary thyroid carcinoma (PTC) after total thyroidectomy implies unsuccessful surgery, indicating a high risk of recurrence. Serum Tg kinetics in such patients have not been extensively studied. We studied serum Tg kinetics in patients with suppressed serum thyrotropin levels and undetectable anti-Tg antibody to minimize the effects of these factors on Tg values, and evaluated the relationship of prognosis to the serum Tg doubling-time. METHODS Between January 1998 and December 2004, 1515 patients with PTC underwent total thyroidectomy in Kuma Hospital. After excluding patients with other thyroid cancers and those positive tests for anti-Tg antibody, there were 426 patients with 4 or more serum Tg measurements at a time that serum thyrotropin concentrations were <0.1 mIU/L. These patients were selected for the present retrospective study. Tg doubling-time was computed using Tg values measured during routine follow-up. Patients were followed for a mean of 88.1 months and a median of 86.7 months. RESULTS Of the 426 patients, 137 patients had 4 or more measurements that revealed detectable Tg in serum Tg. The Tg doubling-time (DT), calculated using all available data, varied widely, and were grouped into those that were <1 year (17 patients), those that were 1-3 years (21 patients), and those that were ≥ 3 years (30 patients), as well as those with a negative value due to decrease in serum Tg (69 patients). There were also 88 patients who had three or fewer serum Tg measurements that showed detectable Tg levels, as well as 201 patients in whom serum Tg measurements were below the lower limit of detection. In the group of patients with a Tg-DT of <1 year the cause specific survival at 10 years was 50%, and in the group with a Tg-DT of 1-3 years it was 95%. In all other groups it was 100%. Many classical prognostic factors (TNM stage, age, and gender) as well as the Tg-DT were significant indicators of survival by univariate analysis, but Tg-DT remained the only independent predictor by multivariate analysis. Tg-DT was also the only independent predictor of distant metastases and loco-regional recurrence on multivariate analysis. Tg-DT calculated using only the first four data [Tg-DT (first four data)] was also the only independent predictor of survival, distant metastases, and loco-regional recurrence on multivariate analysis. CONCLUSIONS Tg-DT (all data or first four data) is a very strong prognostic predictor superior to the classical prognostic factors in patients with PTC.

Risk Factors Contributing to a Poor Prognosis of Papillary Thyroid Carcinoma: Validity of UICC/AJCC TNM Classification and Stage Grouping

BackgroundIn 2002, the UICC/AJCC TNM classification for papillary thyroid carcinoma was revised. In this study, we examined the validity of this classification system by investigating the predictors of disease-free survival (DFS) and cause-specific survival (CSS) in patients.MethodsWe examined various clinicopathological features, including the component of the TNM classification, for 1,740 patients who underwent initial and curative surgery for papillary carcinoma between 1987 and 1995.ResultsClinical and pathological T4a, clinical N1b in the TNM classification, and patient age were recognized as independent predictors of not only DFS, but also CSS of patients. Tumor size, male gender, and central node metastasis independently affected DFS only. There were 1,005 pathological N1b patients, but pathological N1b did not independently affect either DFS or CSS. Regarding the stage grouping, clinical stage IVA including clinical N1b more clearly affected DFS and CSS than pathological stage IVA including pathological N1b.ConclusionClinical stage grouping was more useful than pathological stage grouping for predicting the prognosis of papillary carcinoma patients possibly because pathological stage overestimates the biological characteristics of many pathological N1b tumors.

Induction Chemotherapy with Weekly Paclitaxel Administration for Anaplastic Thyroid Carcinoma

BACKGROUND Anaplastic thyroid carcinoma (ATC) has a very dire prognosis and no effective therapeutic strategies have been established for ATC patients, especially those with stage IVB or IVC. Our objective was to investigate the effectiveness of weekly paclitaxel administered as induction chemotherapy and to establish novel therapeutic strategies for ATC. METHODS We performed induction chemotherapy by weekly paclitaxel administration for patients with stage IVB (nine patients) and IVC (four patients) disease. Clinical and histological responses were assessed. Overall survival was compared with that of ATC patients with stage IVB (n = 50) and IVC (n = 13) treated without paclitaxel. RESULTS One patient demonstrated complete response (CR) and two demonstrated partial response (PR) in the stage IVB group (response rate: 33%), and one patient showed PR in stage IVC (response rate: 25%). Curative surgery and adjuvant therapy were performed for four patients with stage IVB, and 32 months after treatment, all the four are alive and free of disease. One CR patient and one stable disease patient were assessed as grade IV (complete remission) and grade III (nearly CR) on histological response, respectively. All four patients with stage IVC died of carcinoma within 8 months. Overall survival of stage IVB patients with induction chemotherapy was better (p = 0.0213) than that without the chemotherapy and also better (p = 0.0467) than those with chemotherapy other than paclitaxel. However, induction chemotherapy did not improve the overall survival of stage IVC patients (p = 0.2002). CONCLUSIONS Induction chemotherapy by weekly paclitaxel is a promising therapeutic strategy for stage IVB ATC patients. Responders can be expected to achieve long-term survival. We could not get significant difference of overall survival between stage IVC patients with or without weekly induction paclitaxel, although there were some cases that responded well.

Biological behavior and prognosis of familial papillary thyroid carcinoma

BACKGROUND Although the responsible genes have not yet been identified, it is known that the risk of nonmedullary thyroid carcinoma is elevated in individuals with 1st-degree relatives with nonmedullary thyroid carcinoma. However, it remains controversial whether the biological character of familial nonmedullary carcinoma (FNMTC) differs from that of sporadic carcinoma. In this study, we investigated the prevalence of familial papillary carcinoma and its biological behavior. METHODS Between 1987 and 2004, 6,015 patients underwent initial surgical treatment for papillary carcinoma at Kuma Hospital and 273 (4.5%) were classified as having familial carcinoma. We compared the biological characteristics including prognosis between familial and sporadic papillary carcinomas. RESULTS Disease-free survival and cause-specific survival rates of familial carcinoma did not differ from those of sporadic carcinoma. Familial papillary carcinoma showed multicentricity and recurrence to the thyroid more frequently than sporadic carcinoma. There were no differences in other clinicopathological parameters between the 2 groups. CONCLUSION Prognosis of patients with familial papillary carcinoma did not differ from that of those with sporadic papillary carcinoma. Although routine total thyroidectomy is recommended for familial papillary carcinoma, its therapeutic strategy can otherwise be the same as that for sporadic papillary carcinoma.

Incidences of Unfavorable Events in the Management of Low-Risk Papillary Microcarcinoma of the Thyroid by Active Surveillance Versus Immediate Surgery

Background: The incidence of papillary microcarcinoma (PMC) of the thyroid is rapidly increasing globally, making the management of PMC an important clinical issue. Excellent oncological outcomes of active surveillance for low-risk PMC have been reported previously. Here, unfavorable events following active surveillance and surgical treatment for PMC were studied. Methods: From February 2005 to August 2013, 2153 patients were diagnosed with low-risk PMC. Of these, 1179 patients chose active surveillance and 974 patients chose immediate surgery. The oncological outcomes and the incidences of unfavorable events of these groups were analyzed. Results: In the active surveillance group, 94 patients underwent surgery for various reasons; tumor enlargement and the appearance of novel lymph node metastases were the reasons in 27 (2.3%) and six patients (0.5%), respectively. One of the patients with conversion to surgery had nodal recurrence, and five patients in the immediate surgery group had a recurrence in a cervical node or unresected thyroid lobe. All of these recurrences were successfully treated. None of the patients had distant metastases, and none died of the disease. The immediate surgery group had significantly higher incidences of transient vocal cord paralysis (VCP), transient hypoparathyroidism, and permanent hypoparathyroidism than the active-surveillance group did (4.1% vs. 0.6%, p < 0.0001; 16.7% vs. 2.8%, p < 0.0001; and 1.6% vs. 0.08%, p < 0.0001, respectively). Permanent VCP occurred only in two patients (0.2%) in the immediate surgery group. The proportion of patients on L-thyroxine for supplemental or thyrotropin (TSH)-suppressive purposes was significantly larger in the immediate surgery group than in the active surveillance group (66.1% vs. 20.7%, p < 0.0001). The immediate surgery group had significantly higher incidences of postsurgical hematoma and surgical scar in the neck compared with the active surveillance group (0.5% vs. 0%, p < 0.05; and 8.0% vs. 100%, p < 0.0001, respectively). Conclusions: The oncological outcomes of the immediate surgery and active surveillance groups were similarly excellent, but the incidences of unfavorable events were definitely higher in the immediate surgery group. Thus, active surveillance is now recommended as the best choice for patients with low-risk PMC.

Improvement in phonation after reconstruction of the recurrent laryngeal nerve in patients with thyroid cancer invading the nerve

BACKGROUND We report vocal improvement after reconstruction of the recurrent laryngeal nerve (RLN) in patients with nerve resection, although vocal cord movement was not restored. These methods are not widely recognized. METHODS Direct anastomosis, free nerve grafting, or anastomosis to the ansa cervicalis or the vagus nerves with the RLN were performed in 7, 14, 65, and 2 patients with thyroid cancer invading the RLN, respectively. A total of 51 patients had vocal cord paralysis (VCP) pre-operatively. Maximum phonation time (MPT) and vital capacity (VC) were measured before and 1 year after reconstruction. A total of 34 normal subjects and 27 patients with VCP served as controls. RESULTS Patients with VCP had significantly shorter MPT values than normal subjects. At 1 year after operation, patients with reconstruction had values of MPT similar to those of normal subjects. Men had significantly longer MPT values than women, but the phonation efficiency index (PEI), defined as the MPT/VC ratio, did not differ by sex. The PEI was significantly less in VCP patients than in normal subjects. Patients with reconstruction achieved PEI values similar to those in normal subjects. Phonation efficiency index values at 1 year after operation was significantly greater than pre-operative PEI and was not affected by the presence or absence of VCP pre-operatively, age, reconstruction method, thickness of suture thread, or use of magnification during the operation. CONCLUSION In patients with thyroid cancer requiring RLN resection, RLN reconstruction achieved recovery in phonatory function.

Prognosis and prognostic factors of follicular carcinoma in Japan: importance of postoperative pathological examination.

BackgroundFollicular carcinoma is known to show a worse prognosis than papillary carcinoma because of distant metastasis in higher incidence. However, few studies have been published regarding the prognosis of follicular carcinoma patients in Japan, which prompted us to investigate this issue.MethodsWe examined the prognosis and whether and how various clinicopathological features have affected disease-free survival (DFS) and cause-specific survival (CSS) of 334 patients who underwent initial surgery for follicular carcinoma.ResultsIn 18 patients (5.4%), curative surgery could not be achieved because of distant metastasis at surgery in 17 patients and local extension in 1 patient. For 316 patients who underwent curative surgery, 5-year and 10-year DFS rates were 88.4% and 75.3%, respectively. Poorly differentiated carcinoma and widely invasive carcinoma, together with some conventional prognostic factors, predicted poorer DFS of patients. On multivariate analysis, poorly differentiated carcinoma was an independent prognostic factor for DFS. The 5-year and 10-year CSS rates for these 334 patients were 96.4% and 90.4%, respectively. Curative surgery and poorly differentiated carcinoma were recognized as independent prognostic factors.ConclusionsWe can hypothesize that follicular carcinoma in Japan is generally a nonaggressive disease with a good prognosis. However, because poorly differentiated or widely invasive carcinomas showed a worse prognosis, postoperative pathological examination is important in predicting patient prognosis.

Extranodal tumor extension to adjacent organs predicts a worse cause-specific survival in patients with papillary thyroid carcinoma

BackgroundWe previously reported that massive extrathyroid extension has an independent prognostic value in patients with thyroid papillary carcinoma. However, tumor extension to adjacent organs can be observed not only in primary tumor but also in metastatic nodes. In this study we investigated the clinical significance of extranodal tumor extension to adjacent organs (nodal ex) in papillary thyroid carcinoma.MethodsWe classified all cases into three categories based on the degree of nodal ex: nodal ex0, no apparent extranodal tumor extension; nodal ex1, hard metastatic nodes with perinodal growth extending to adjacent organs, which require separation of the nodes from the organs; and nodal ex2, metastatic nodes with perinodal growth completely invading the adjacent organs and requiring excision of nodes together with these organs. We investigated the clinical significance of each grade in 1,692 patients who underwent initial surgery for papillary carcinoma between 1987 and 1995.ResultsThe presence of nodal ex was significantly linked to various clinicopathological features such as male gender, N1b, large number of metastatic nodes, pT4a, and distant metastasis. On univariate analysis, patients with either nodal ex1 or ex2 showed significantly worse disease-free and cause-specific survival rates, although these rates did not differ between patients with nodal ex1 and those with nodal ex2. Furthermore, multivariate analysis demonstrated that nodal ex independently predicts worse cause-specific survival of these patients.ConclusionsPresence of nodal ex significantly reflects the biologically aggressive behaviors of papillary carcinoma and has a prognostic value, especially for cause-specific survival of patients.