Patients with PTC who underwent thyroid surgery between January 2005 and December 2006 at Yonsei University Hospital, Seoul, Korea were enrolled. All patients underwent pre-operative ultrasonography and fine needle aspiration cytology (FNAC) of the primary tumor, and were diagnosed with PTC pathologically. Of these patients, excluding patients with another subtype of thyroid carcinoma and a variant of PTC, and patients who had been diagnosed with CLT or any thyroid disease before being diagnosed with PTC were also excluded to prevent selection bias, because they had more opportunity for early detection of PTC that could lead to better treatment outcomes. A total 1,357 patients who received initial treatment for PTC at our institution and whose medical records were accessible for review as included in the first study arm to identify clinical characteristics of coexistent CLT in PTC patients at the time of surgery.

Among these 1,357 patients, those who were lost to follow-up, who had a history of the coexistence of another cancer, and who revealed lateral neck LN metastasis or distant metastasis at the time of surgery were excluded. Five hundred ninety seven consecutive patients with PTC who underwent total thyroidectomy with prophylatic ipsilateral central compartment node dissection followed by immediate ¹³¹I remnant ablation were enrolled in the second study arm to evaluate the influence on prognostic outcome of coexistent CLT in PTC patients.

Patient data were collected by retrospective medical record review. Patient demographics (age and gender), histopathological findings (tumor size, extrathyroidal extension, multifocality, LN metastasis and presence of CLT), preoperative laboratory finding (thyroid stimulating hormone [TSH], anti-thyroglobulin [Tg] autoantibody and anti-microsomal autoantibody) and clinical outcomes (loco-regional recurrences and distant metastasis) were analyzed. Pathologic staging was defined according to the Tumor, LN, and Metastasis (TNM) classification system based on the 6th edition of the UICC/AJCC TNM classifications. In addition, two well-established prognosis classification systems of differentiated thyroid cancer - the low/high risk group determination based on the Age, Metastasis, Extent of disease, Size (AMES) stage system (15) and the Metastasis, Age at presentation, Completeness of surgical resection, Invasion (extrathyroidal extension), Size (MACIS) formula-based scoring system (16) - were used to analyze various clinicopathological parameters. The systems have established that high scores are strongly correlated with a poor prognosis. Serum anti-microsomal and anti-Tg antibody analysis was performed by radioimmunoassay with commercial kits (Brahms, Berlin, Germany). TSH level was determined by an immunoradiometric assay (Coat-ACount, TSH IRMA; DPC, Los Angeles, CA, USA). The analytical sensitivity of the assay for anti-microsomal antibody, anti-Tg and TSH was 5.5, 5.5, and 0.3 IU/mL, respectively. The intraassay coefficients of variation ranged from 2.9%-4.5%, 2.0%-7.5%, and 1.9%-5.8%, respectively. The reference ranges for both anti-microsomal antibody and antithyroglobulin were < 60 IU/mL and for TSH 0.3-5.0 mL/L.

The diagnosis of CLT was obtained from a review of the pathologic slides by one pathologist. Pathologically proven CLT was defined as the presence of diffuse lymphoplasmacytic infiltrate, oxyphilic cells, formation of lymphoid follicles with germinal centers and atrophic changes in the area of normal thyroid tissue. Only peri-tumoral lymphocytic infiltration was not considered as CLT (2, 3, 9, 17).

At our institution, thyroid resection consisted of total thyroidectomy and less than total thyroidectomy. The definition of "less than total thyroidectomy" is specified by unilateral thyroid lobectomy, ipsilateral total and contralateral partial thyroidectomy, and ipsilateral total and contralateral subtotal thyroidectomy. Thyroid lobectomy with isthmusectomy was performed only when the following criteria were met: the cancer was an intrathyroidal, unifocal micro-carcinoma (< 1 cm), with no cervical lymph node involvement. In other cases, total thyroidectomy was performed. Ipsilateral central compartment node dissection was performed in all cases. If the patients have evidence of lateral lymph node metastasis in preoperative evaluation, Modified radical neck dissection was performed. The choice of surgical extension was based on ATA guidelines (18). During thyroid resection, only central compartment lymph nodes (CCLN) located in the ipsilateral site of the primary tumor were dissected prophylatically. The CCLN or level VI included the pretracheal, paratracheal, prelaryngeal, perithyroidal nodes, and lymph nodes located along the recurrent laryngeal nerve. The central compartment was delimited superiorly by the hyoid bone, inferiorly by the substernal notch, laterally by the median portion of the carotid sheath, and dorsally by the prevertebral fascia. Recurrent laryngeal nerves and parathyroid glands were identified and preserved in all cases. The procedures were performed by the same surgical team. If patients had evidence of lateral LN metastasis in preoperative evaluation, modified radical neck dissection was performed. Radioactive iodine remnant ablation was performed within 6 weeks after surgery. Indication for radioiodine ablation in this cohort of patients was based on ATA guidelines (18). A ¹³¹I whole body scan was taken on day 2 following radioiodine therapy. All patients received thyroid-stimulating hormone suppression treatment with levothyroxine according to ATA guidelines. Patient follow-up was based on physical examination, neck ultrasound (US), and serum Tg measurement at intervals of 3 or 6 months.

Statistical analysis was performed using SPSS (version 14.0; SPSS, Chicago, IL, USA). Continuous data are represented as mean ± standard deviation. To compare continuous variables, age, tumor size and mean, MACIS scores according to CLT status were tested using an independent t-test. The association between CLT (present or absent) and prognostic variables was assessed using a chi-squared test or Fisher's exact test for gender, extrathyroidal extension, multifocality, LN metastasis, TNM and AMES stage. The Kaplan-Meyer method with a log-rank test was used to account for recurrence and disease free rates during the follow-up period. Statistically significant variables based on univariate analysis were included in a multivariate analysis using a binary logistic regression test. With regard to the results, P values were two-sided throughout and the statistical significance was defined as P < 0.05.

This study was approved by the institutional review board of Severance Hospital, Yonsei University College of Medicine in Seoul, Korea (IRB number: 4-2011-0879). All participants gave their written informed consent.

Among the 1,357 patients, there were 181 men and 1,176 women. Mean age was 45.53 yr. The mean tumor size was 1.08 ± 0.77 cm. Multifocality, extrathyroidal extension and LN metastasis were detected in 450 (33.2%), 752 (55.4%) and 619 patients (45.6%), respectively. Three hundred fifty nine (26.5%) of 1,357 patients with PTC had co-existing CLT. Based on univariate analysis, the mean age of patients with and without CLT was 44.50 ± 10.65 and 45.90 ± 11.68 yr, respectively (P = 0.047). Predominance of female gender was observed in patients with CLT compared to patients without CLT (P = 0.001). The mean tumor size was smaller in patients with CLT than patients without CLT (1.01 ± 0.66 cm vs 1.10 ± 0.81 cm, respectively; P = 0.040). The prevalence of extrathyroidal extension was higher in patients without CLT (P = 0.016). There was no statistically significant difference in the prevalence of operation methods, multifocality and TNM stage between the two groups (P = 0.094, 0.845, and 0.781, respectively). The rate of total LN metastasis was not significantly different in patients with and without CLT patients (P = 0.294). There was no difference in the prevalence of central LN metastasis and lateral LN metastasis between the two groups (P = 0.322 and 0.252, respectively). Table 1 summarizes the results of the univariate analyses.

The clinical and pathological parameters of the second study cohort are summarized in Table 2. When total thyroidectomy patients results were compared with the results from the total patient population, the prevalence of women and small tumor size were evident in the group of patients who had PTC with CLT (P = 0.001 and 0.035, respectively), although there was no difference in extrathyroidal extension and age between the two groups (P = 0.724 and 0.153, respectively). There was no difference in the prevalence of LN metastasis, multifocality and TNM stage between the two groups (P = 0.784, 0.316, and 0.620, respectively). However, LN metastasis ratio (metastatic LN number/dissected LN number) was lower in patients with CLT compared to patients without CLT (P = 0.001). The recurrence rate in the patients with CLT (1.5%) was lower than that in without CLT (5.0%) (P = 0.042).

Evaluation of the expected prognostic outcome using the AMES (15) clinical staging system and the MACIS scoring system (16) was also performed. With the AMES staging system, the proportion of high-risk group of patients with PTC alone was higher than that of patients with PTC and CLT (31.3% and 21.0%, respectively; P = 0.009). Using the MACIS scoring system, the proportion of the high-risk group of patients with PTC alone was also higher than that of patients with PTC and CLT. Patients with PTC alone exhibited a higher mean score (4.89 vs 4.74; P = 0.049) and a higher percentage (15.4% vs 7.2%) of the patients scoring ≥ 6 on the MACIS scoring system (P = 0.004; Table 3).

All patients in whom recurrence was suspected were confirmed using cytology and/or histology. During the mean 58-month follow-up period in the PTC with CLT group, three (1.5%) of 195 patients experienced recurrence and all of the recurrent diseases occurred at the ipsilateral lateral LN. Comprehensive neck dissection followed by high-dose radioactive iodine remnant ablation therapy was performed in all of these patients, and none have died at the time of the present evaluation. Of the patients in PTC without CLT with a mean 58-month follow-up period, a total of 20 (5.0%) have experienced recurrence, the main locations were the regional LN (18 patients; 3 patients = ipsilateral central LN, 15 patients = ipsilateral lateral LN), and 2 patients had distant lung metastasis. Comprehensive neck dissection followed by high-dose radioactive iodine remnant ablation therapy was performed in all of these patients, and none have died at the time of the present evaluation. Patients with PTC and CLT tended to have a better prognosis compared with that of patients with PTC alone. Disease free survival (DFS) rate in the patients with CLT was significantly higher than that without CLT during follow-up period (log-rank = 4.11, P = 0.042; Fig. 1). DFS was evaluated according to the presence or absence of LN metastasis at the time of surgery. Especially in PTC patients with central LN metastasis, DFS was significantly higher in patients with CLT compared with those without CLT (log-rank = 4.31, P = 0.038; Fig. 2).

We separately analyzed the outcomes for lower-risk group and high-risk groups by AMES stage and MACIS scoring systems. In lower-risk patients, DFS was significantly different in patients with CLT compared with those without CLT (P = 0.009 and P = 0.018, respectively). But, there were no significant differences in high-risk patients with CLT compared with those without CLT by AMES stage and MACIS scoring system (P = 0.778 and P = 0.456, respectively).

Based on univariate analysis, LN metastasis (P = 0.001, odds ratio [OR] = 9.676) and CLT (P = 0.042, OR = 0.298) were observed in patients with recurrence compared with patients without recurrence. However, gender (i.e., prevalence of females), extrathyroidal extension, age, tumor size and multifocality were not significantly different based on the univariate analysis between the two groups (Table 4). However, based on multivariate analysis, only LN metastasis (P = 0.001, OR = 9.278) was observed in patients with recurrence compared with patients without recurrence. The multivariate analysis did not show a negative association between the coexistence of CLT and recurrence.

We analyzed the CLT patients separately to evaluate the correlation between pathologic diagnosis and laboratory finding. CLT patients who were confirmed pathologically were divided into group A (anti-Tg Ab and anti-microsomal Ab were all negative) and group B (anti-Tg Ab positive or anti-microsomal Ab positive). In group A patients, CLT was confirmed by pathological examination but laboratory examination was negative, while CLT was confirmed in group B patients by pathological and laboratory examinations. The clinical and pathological parameters are summarized in Table 5. There was no statistically significant difference in age, gender, size, prevalence of extrathyroidal extension, multifocality, LN metastasis, TNM stage and recurrences between the two groups.