Brian Hung-Hin Lang

Staging Systems for Papillary Thyroid Carcinoma : a review and comparison

Objective:To find out the most predictive staging system for papillary thyroid carcinoma (PTC) currently available in the literature. Background:Various staging systems or risk group stratifications have been used extensively in the clinical management of patients with PTC, but the most predictive system for cancer-specific survival (CSS) based on distinct histologic types remains unclear. Methods:Through a comprehensive MEDLINE search from 1965 to 2005, a total of 17 staging systems were found in the literature and 14 systems were applied to the 589 PTC patients managed at our institution from 1961 to 2001. CSS were calculated by Kaplan-Meier method and were compared by log-rank test. Using Cox proportional hazards analysis, the relative importance of each staging system in determining CSS was calculated by the proportion of variation (PVE). Results:All 14 staging systems significantly predicted CSS (P < 0.001). The 3 highest ranked staging systems by PVE were the Metastases, Age, Completeness of Resection, Invasion, Size (MACIS) (18.7) followed by the new AJCC/UICC 6th edition tumor, node, metastases (TNM) (17.9), and the European Organization for Research and Treatment of Cancer (EORTC) (16.6). Conclusions:All of the currently available staging systems predicted CSS well in patients with PTC regardless of which histologic type from which they were derived. When predictability was measured by PVE, the MACIS system was the most predictive staging system and so should be the staging system of choice for PTC in the future.

Prognostic Factors in Papillary and Follicular Thyroid Carcinoma: Their Implications for Cancer Staging

Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are two distinct histological types of thyroid carcinoma but have often been studied and staged as a collective group, known as differentiated thyroid carcinoma (DTC). However, this may not be an optimal approach to cancer staging. A total of 760 patients with DTC, comprising 589 (77.5%) with PTC and 171 with (22.5%) FTC, being managed at our institution from 1961 to 2001 were retrospectively reviewed. Their clinicopathological features, treatment modalities received, and postoperative outcome were analyzed. Both univariate and multivariate analyses were performed to identify prognostic factors related to cancer-specific survival (CSS) for PTC and FTC. There were statistically significant differences between PTC and FTC in terms of age ≥50 years at diagnosis (P = .040), tumor size (P < .001), lymph node metastases (P < .001), distant metastases (P < .001), extrathyroidal extension (P < .001), multifocality (P = .002), capsular invasion (P < .001), extent of thyroid resection (P < .001), radioiodine ablation (P < .001), and external-beam irradiation (P = .003). Although PTC and FTC had similar 10-year and 15-year CSS (P = .846), each possessed its own set of independent prognostic factors for CSS. Age at diagnosis and completeness of resection were independent prognostic factors in both PTC and FTC. There were marked differences in clinicopathologic features, treatment, and prognostic factors between the two histologic types of DTC. Different staging systems should be evaluated and validated for PTC and FTC individually in the future.

Classical and follicular variant of papillary thyroid carcinoma: a comparative study on clinicopathologic features and long-term outcome.

IntroductionThe follicular variant of papillary thyroid carcinoma (FVPTC) is the most common histologic subtype of papillary thyroid carcinoma (PTC). However, it is still controversial whether FVPTC should behave differently from classical PTC (CPTC). The present study aimed at evaluating any potential difference in clinicopathologic features and long-term outcome of FVPTC as compared with CPTC.Patients and MethodsOf 568 patients with PTC managed from 1973 to 2004, 308 were shown to have CPTC (54.2%) and 67 (11.8%) FVPTC after histologic review. The mean (± SD) follow-up period was 11.3 (± 8.9) years. The two groups were compared in terms of clinicopathological features, treatment received, and outcome regarding recurrence and disease-specific survival.ResultsThere was no difference in age and gender ratio between the CPTC and FVPTC patients. Both groups had similar tumor characteristics in terms of tumor size, presence of multifocality, capsular invasion, lymphovascular permeation, and perineural infiltration. However, FVPTC patients had significantly fewer histologically confirmed cervical lymph node metastases (P = 0.027) and extrathyroidal involvement (P = 0.005). The proportion of bilateral resection, adjuvant radioactive iodine, and lymph node dissection did not differ significantly between the two groups. The FVPTC patients had a more favorable tumor risk by DeGroot classification (P = 0.003) and MACIS (Metastasis, Age, Completeness of excision, Invasiveness, and Size) score (P = 0.026). The 10- and 15-year actuarial disease-specific survivals did not differ significantly between FVPTC and CPTC patients (96.2% versus 90.7% and 96.2% versus 89.1%, respectively).ConclusionsAlthough patients with FVPTC had more favorable clinicopathologic features and a better tumor risk group profile, their long-term outcome was similar to that of CPTC patients.

A systematic review and meta-analysis of prophylactic central neck dissection on short-term locoregional recurrence in papillary thyroid carcinoma after total thyroidectomy.

BACKGROUND Prophylactic central neck dissection (pCND) at the time of total thyroidectomy (TT) remains controversial in clinically node-negative (cN0) papillary thyroid carcinoma (PTC). Despite occult central lymph node metastases being common, it is unclear if removing these metastases initially would reduce future locoregional recurrence (LRR). This systematic review and meta-analysis aimed at comparing the short-term LRR between patients who underwent TT with pCND and those who underwent TT alone. METHODS A systematic review of the literature was performed to identify studies comparing LRR between patients with PTC who underwent TT + pCND (group A) and those who underwent TT alone (group B). Inclusion criteria were cN0 patients, with each comparative group containing > 10 patients, and with the number of LRR and mean follow-up duration available. The pooled incidence rate ratio (IRR) was used for calculating the LRR rate between the two groups. Other parameters evaluated included postoperative radioiodine (RAI) ablation, surgically related complications, and overall morbidity. Meta-analysis was performed using a fixed-effects model. RESULTS Fourteen studies matched the selection criteria. Of the 3331 patients, 1592 (47.8%) belonged to group A, while 1739 (52.2%) belonged to group B. Relative to group B, group A was significantly more likely to have postoperative RAI ablation (71.7% vs. 53.1%; odds ratio [OR] = 2.60 [95% confidence interval (CI) = 2.12-3.18]), temporary hypocalcemia (26.0% vs. 10.8%; OR = 2.56 [CI = 2.04-3.21]), and overall morbidity (33.2% vs. 17.7%; OR = 2.12 [CI = 1.75-2.57]). When temporary hypocalcemia was excluded, overall morbidity was similar between the two groups (7.3% vs. 6.8%; OR = 1.07 [CI = 0.78-1.47]). Group A had a significantly lower risk of LRR than group B (4.7% vs. 8.6%; IRR = 0.65 [CI = 0.48-0.86]). CONCLUSIONS Group A was more likely to have postoperative RAI ablation, temporary hypocalcemia, and overall morbidity than group B. Temporary hypocalcemia was the major surgical morbidity in pCND and, when excluded, the overall morbidity appeared similar between the two groups. Although our meta-analysis would suggest that those who undergo TT + pCND may have a 35% reduction in risk of LRR than those who undergo TT alone in the short term (< 5 years), it remains unclear how much of this risk reduction is related to increased use of RAI ablation and potential selection bias in some of the studies examined.

Papillary Microcarcinoma: Is There Any Difference between Clinically Overt and Occult Tumors?

Papillary microcarcinoma (PMC) is a subtype of papillary thyroid carcinoma (PTC) associated with excellent prognosis. However, clinical and biologic behaviors of PMC may vary considerably between tumors that are clinically overt and those that are occult. From 1964 to 2003, 185 of 628 patients with PTC were identified as having PMC, based on tumor size ≤1 cm. There were 110 overt and 75 occult PMCs detected based on clinical presentation. The clinicopathologic features, treatment, and long-term outcome of PMCs were evaluated and compared between the two groups. There were 37 men and 148 women with a median age of 45 years (range: 11–84 years). The median tumor size was 6.2 mm. Thirty-eight (21%) patients presented with cervical nodal metastases. Three (1.6%) had distant metastases and 5 (2.7%) underwent incomplete resection. Bilateral procedures were performed for 129 patients (70%) and 53 (29%) received postoperative I131treatment. During a mean follow-up of 8.2 years, 4 patients died of the disease and 13 developed recurrence. Clinically overt PMCs were significantly larger, were more likely to be multifocal, and more likely to lead to bilateral thyroidectomy. Extrathyroidal or lymphovascular invasion, nodal metastases, I131ablation, high-risk tumors, and postoperative recurrence occurred in overt PMC only. Patients with nodal metastases had a decreased survival and an increase in locoregional recurrence. Despite a relatively good prognosis in PMC, a distinction should be made between clinically overt and occult PMCs in which clinically overt PMC should be managed according to tumor risk profile and clinical presentation.

A Germline Mutation (A339V) in Thyroid Transcription Factor-1 (TITF-1/NKX2.1) in Patients With Multinodular Goiter and Papillary Thyroid Carcinoma

BACKGROUND The genetic factors that determine the risk of papillary thyroid carcinoma (PTC) among patients with multinodular goiter (MNG) remain undefined. Because thyroid transcription factor-1 (TTF-1) is important to thyroid development, we evaluated whether the gene that encodes it, TITF-1/NKX2.1, is a genetic determinant of MNG/PTC predisposition. METHODS Twenty unrelated PTC patients with a history of MNG (MNG/PTC), 284 PTC patients without a history of MNG (PTC), and 349 healthy control subjects were screened for germline mutation(s) in TITF-1/NKX2.1 by sequencing of amplified DNA from blood. The effects of the mutation on the growth and differentiation of thyroid cells were demonstrated by ectopic expression of wild-type (WT) and mutant proteins in PCCL3 normal rat thyroid cells, followed by tests of cell proliferation, activation of cell growth pathways, and transcription of TTF-1 target genes. All statistical tests were two-sided. RESULTS A missense mutation (1016C>T) was identified in TITF-1/NKX2.1 that led to a mutant TTF-1 protein (A339V) in four of the 20 MNG/PTC patients (20%). These patients developed substantially more advanced tumors than MNG/PTC or PTC patients without the mutation (P = .022, Fisher exact test). Notably, this germline mutation was dominantly inherited in two families, with some members bearing the mutation affected with MNG, associated with either PTC or colon cancer. The mutation encoding the A339V substitution was not found among the 349 healthy control subjects nor among the 284 PTC patients who had no history of MNG. Overexpression of A339V TTF-1 in PCCL3 cells, as compared with overexpression of WT TTF-1, was associated with increased cell proliferation including thyrotropin-independent growth (average A339V proliferation rate = 134.27%, WT rate = 104.43%, difference = 34.3%, 95% confidence interval = 12.0% to 47.7%, P = .010), enhanced STAT3 activation, and impaired transcription of the thyroid-specific genes Tg, TSH-R, and Pax-8. CONCLUSION This is the first germline mutation identified in MNG/PTC patients. It could contribute to predisposition for MNG and/or PTC and to the pathogenesis of PTC.

A prospective, assessor-blind evaluation of surgeon-performed transcutaneous laryngeal ultrasonography in vocal cord examination before and after thyroidectomy

INTRODUCTION Transcutaneous laryngeal ultrasonography (TLUSG) is a promising alternative to direct laryngoscopy in assessing perioperative vocal cord function. This study sought to evaluate the accuracy of TLUSG in assessing vocal cord function. METHODS Altogether, 204 patients underwent TLUSG and direct laryngoscopy before and after elective thyroidectomy. For both examinations, vocal cord movements were independently graded. Grade I meant both vocal cords had normal movement; grade II meant ≥1 vocal cord had decreased movement; and grade III meant ≥1 vocal cord had no movement. Grade II or III on direct laryngoscopy was defined as vocal cord paresis or palsy (VCP). To assess accuracy, TLUSG findings were correlated with direct laryngoscopy findings. RESULTS No patient had preoperative VCP, and 17 had unilateral postoperative VCP. The overall postoperative VCP rate was 5.1%. TLUSG failed to assess VCs in 11 (5.4%) postoperative patients. Of these, 2 had VCP and 9 had no VCP on direct laryngoscopy. Postoperative TLUSG had a sensitivity, specificity, positive predictive value, and negative predictive value of 93.3%, 97.8%, 77.8%, and 99.4%, respectively. Of the 175 patients with grade I on TLUSG, only 1 (<1%) had grade II VCP on direct laryngoscopy. CONCLUSION TLUSG is a promising, noninvasive tool for selecting patients to undergo direct laryngoscopy before and after thyroidectomy.

Risk of second primary malignancy in differentiated thyroid carcinoma treated with radioactive iodine therapy.

BACKGROUND Differentiated thyroid cancer survivors are at increased risk of nonsynchronous second primary malignancy, but the cause remains unclear. This study aimed to evaluate the association between radioiodine therapy and risk of nonsynchronous second primary malignancy and to examine whether the risk of nonsynchronous second primary malignancy in differentiated thyroid cancer survivors treated with radioiodine therapy is increased relative to the general population. METHODS Among 895 radiation-naïve patients with differentiated thyroid cancer, 643 (71.8%) received ≥1 course of radioiodine therapy (radioiodine therapy-positive group) and 252 (28.2%) received no radioiodine therapy (radioiodine therapy-negative group). After a median follow-up of 93.5 months (range, 23.4-570.8), 64 (7.2%) patients developed ≥1 nonsynchronous second primary malignancy. Potential risk factors for nonsynchronous second primary malignancy were entered into a multivariable regression model and cancer incidence in the radioiodine therapy-positive and -negative groups were compared to that of the general population by estimating the standardized incidence ratios. RESULTS The 20-year cumulative nonsynchronous second primary malignancy risk in radioiodine therapy-positive group was significantly higher than radioiodine therapy-negative group (13.5% vs 3.1%; P = .015). Cumulative radioiodine therapy activity of 3.0 to 8.9 GBq (relative risk, 2.77; 95% CI, 1.079-7.154; P = .034) was the only independent risk factor for nonsynchronous second primary malignancy after adjusting for age, sex, period of differentiated thyroid cancer diagnosis, and stage of differentiated thyroid cancer. For females, the standardized incidence ratio in the radioiodine therapy-positive group was 1.54 (95% CI, 1.11-2.08) and in the radioiodine therapy-negative group it was 0.92 (95% CI, 0.37-1.90). CONCLUSION Differentiated thyroid cancer female survivors treated by radioiodine therapy appeared to be at elevated risk of nonsynchronous second primary malignancy when compared to the general population and this risk was not apparent in those not previously treated by radioiodine therapy.

Staging Systems for Papillary Thyroid Carcinoma: A Study of 2 Tertiary Referral Centers

Objective:To find out the most applicable and consistent staging system for papillary thyroid carcinoma (PTC) available in the literature. Background:The commonly used staging systems for PTC have predicted cancer-specific survival (CSS) well. However, their applicability and generalizability have not yet been evaluated in different clinical settings. Methods:A MEDLINE search from 1965 to 2005 was carried out to identify different staging systems available in the literature and 9 systems were applicable to 1634 PTC patients within 2 tertiary-referral centers. The CSS of each staging system within individual centers were calculated using Kaplan-Meier method and the CSS of each tumor stage in one individual center was compared with that of the other by log-rank test. In addition, within each center, the predictability of each staging system relative to the others was ranked based on the proportion of variation explained (PVE) value. Results:Clinicopathologic features, treatment received, and tumor stages were significantly different between the 2 centers. There were also significant differences in CSS within at least one tumor stage between the 2 centers in 8 of the 9 staging systems. The TNM was a highly predictive and consistent staging system within the 2 centers. Although the absolute PVE values differed between the 2 centers, the relative ranking of the 9 staging systems within each center correlated significantly to each other (P < 0.05). Conclusions:Despite referral, treatment, and data collection biases inherent within each center, the TNM system remained to be the most applicable and consistent staging system for PTC in 2 centers managing the same population group.

Restaging of Differentiated Thyroid Carcinoma by the Sixth Edition AJCC/UICC TNM Staging System: Stage Migration and Predictability

The AJCC/UICC TNM staging system (TNM) is a widely accepted system for differentiated thyroid carcinoma (DTC). The objective of the present study was to evaluate the potential changes in cancer-specific survival (CSS) after reclassification from fifth to sixth edition TNM. A total of 760 DTC patients managed at our institution from 1961 to 2001 were retrospectively restaged from the fifth to sixth edition TNM. CSS were calculated using Kaplan–Meier method and were compared by the log-rank test. The relative ability of each edition in predicting CSS was calculated by the proportion of variance explained (PVE). Upon reclassification, the proportion of T1 and T3 tumors increased from 14.2 to 33.4% and 10.0 to 33.7%; T2 and T4 decreased from 44.2 to 25.0% and 31.6 to 7.9%, respectively; N0 remained unchanged at 66.0%; N1a decreased from 25.7 to 4.7%; N1b increased from 8.4 to 29.3%; stages I and IV tumors increased from 55.7 to 60.3% and 3.4 to 17.6%, respectively; stages II and III tumors decreased from 20.5 to 13.9% and 20.4 to 8.2%, respectively. The sixth edition had a higher PVE value than the fifth edition. Significant differences in CSS were observed between stage III (fifth edition) and stage III (sixth edition) and between stage IV (fifth edition) and stage IVA (sixth edition). The sixth edition TNM caused marked changes in the pT, pN and allocation of patients into different tumor stages. It appeared to have superior predictability over the fifth edition.