Clinical Presentations and Outcomes of Surgical Treatment of Follicular Variant of the Papillary Thyroid Carcinomas

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1 Clinical Presentations and Outcomes of Surgical Treatment of Follicular Variant of the Papillary Thyroid Carcinomas Hung-Yu Chang 1, Jen-Der Lin 1, Shuo-Chi Chou 1, Tzu-Chieh Chao 2 and Chuen Hsueh 3 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan Hsien, 2 Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan Hsien and 3 Department of Pathology, Chang Gung Memorial Hospital, Taoyuan Hsien, Taiwan, ROC Received February 17, 2006; accepted July 15, 2006; published online September 25, 2006 Jpn J Clin Oncol 2006;36(11) doi: /jjco/hyl093 INTRODUCTION Background: The follicular variant of papillary thyroid carcinoma (FVPTC) presents with biological and morphological features similar to papillary thyroid carcinoma. Pre-operative diagnosis of FVPTC and its clinical course is important in identifying appropriate surgical procedures. Methods: This study enrolled 85 patients, 68 females (mean age years) and 17 males (mean age years) with papillary thyroid carcinomas diagnosed as FVPTC. From the patient database at Chang Gung Medical Center (CGMC), 170 pure papillary thyroid carcinoma cases and 85 with minimally invasive follicular thyroid carcinomas of gender- and age-matched patients were randomly selected as control groups. All patients were categorized into high- and low-risk groups according to AMES criteria. Results: Of the three groups, 7.1% (follicular), 11.8% (FVPTC) and 34.1% (pure papillary thyroid carcinoma) of patients presented with lymph node or soft tissue invasion (P ¼ ). Additionally, 29.4, 11.8 and 2.4% of patients with follicular carcinoma, FVPTC and pure papillary thyroid carcinoma, respectively, presented with distant metastases at the time of diagnosis. Of the 85 FVPTC cases, 75 underwent pre-operative fine needle aspiration cytology (FNAC) examination at CGMC. Only 11 cases were diagnosed pre-operatively with papillary thyroid carcinomas. Kaplan Meier survival curves for these three groups demonstrated that follicular thyroid carcinoma had a prognosis worse than both papillary thyroid carcinomas. Conclusions: Most FVPTC cases were diagnosed as follicular neoplasm via pre-operative FNAC. In this study, FVPTC patients had a high ratio of distant metastases, few lymph node metastases and soft tissue invasion. Aggressive treatment was indicated for the high-risk FVPTC patients. Key words: fine needle aspiration cytology thyroglobulin radioactive iodine thyroidectomy prognostic factors Papillary and follicular thyroid carcinomas are the most common thyroid cancers in most regions worldwide. Increased incidence and decreased mortality due to papillary or follicular thyroid carcinoma were reported recently (1, 2). The clinical features and prognoses for papillary and follicular thyroid carcinomas differ considerably. Approximately 1 8% of papillary and 8 33% of follicular thyroid carcinoma patients present with distant metastases at diagnosis (3 5). In 1977, Chen et al. recognized a follicular variant of papillary thyroid carcinoma (FVPTC) with the biological For reprints and correspondence: Jen-Der Lin, Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, 5, Fu-Shin St, Kweishan County, Taoyuan Hsien, Taiwan, R.O.C. einjd@adm.cgmh.org.tw and morphological features characteristic of papillary thyroid carcinoma (6). Controversy is evident in recent studies regarding the long-term survival and prognosis for FVPTC and pure papillary thyroid carcinoma patients (7, 8). This study retrospectively analyzed and compared the clinical presentations of and surgical outcomes for pure papillary, follicular thyroid carcinoma and FVPTC. PATIENTS AND METHODS Data were collected for thyroid cancer patients treated at Chang Gung Medical Center (CGMC), Linkou, Taiwan. Information for 2279 patients with pathologically confirmed thyroid cancer was collected between 1980 to the end of Of these, 1723 were diagnosed with papillary # 2006 Foundation for Promotion of Cancer Research

2 Jpn J Clin Oncol 2006;36(11) 689 carcinomas, including 85 consecutive FVPTC patients. Patients who did not attend regular follow-up for more than one year were excluded. Disease status of patients was thus ascertained and these patients were asked to undergo a follow-up examination. To compare the clinical presentations and treatment outcomes, 170 gender- and age-matched patients with pure papillary thyroid carcinoma and 85 with minimally invasive follicular thyroid carcinoma were randomly selected from this patient database. Other histological variants of papillary thyroid carcinoma, such as tall cell variant, columnar cell variant or undifferentiated patterns, were excluded from control groups. In this study, TNM staging was utilized as previously described (9). All patients were classified as disease free or non-disease free based on their medical records at the end of All patients were assigned to a high- or low-risk group according to AMES criteria (10). The clinical practice of using fine needle aspiration cytology (FNAC) was applied to subjects suspected of having thyroid nodules. Needles of 22-gauge were used without local anesthesia. In cases with profuse bleeding, a 25-gauge needle was utilized. All aspirated fluid was removed when cystic lesions were encountered. Unless refused by the patient, FNAC was performed on all nodules detected by ultrasonography. If the nodule size exceeded 2.5 cm with hypo-echogenecity, nodules were aspirated twice when possible. Aspirate was expressed on frosted-end glass slides, dried in air and stained, using the Romanowsky-based method as described by Liu (11). A retrospective review was performed of pre-operative aspiration cytology that demonstrated FVPTC by final histopathology. A scoring system based on cell abundance, follicular arrangement, nuclear grooves, inclusion bodies and chewinggum colloid was used. At CGMC, most patients diagnosed with welldifferentiated thyroid cancer before or during surgery underwent near total thyroidectomy. Following surgery, most patients prescribed long-term thyroid hormone replacement or suppressive treatment. Cancer assessments involved a 2 5 mci 131 I whole body scan and chest X-ray. Serum thyroglobulin (Tg) levels were assessed every 6 12 months. Post-operative serum Tg levels were detected with an IRMA kit (CIS Bio International, France). The following patient data was obtained from patients medical records: age, gender, primary tumor size, ultrasonographic findings, FNAC results, thyroid function before surgery, operative techniques, histopathology findings, TNM staging, onemonth post-operative serum Tg levels, results of diagnostic and therapeutic 131 I scanning, post-operative chest X-ray findings, clinical status for analysis of distant metastases by non-invasive examinations, treatment outcomes, causes of death and survival status. All data are expressed as mean + SEM. Univariate statistical analysis of the significance of variables was performed using the Kaplan Meier method and log rank test (12, 13). Statistical significance was P Disease free survival and carcinoma-specific survival for FVPTC, pure papillary thyroid carcinoma and follicular thyroid carcinoma was estimated by the Kaplan Meier method and compared using the Mantel Cox method. RESULTS In total, 85 patients with papillary thyroid carcinomas diagnosed as FVPTC underwent surgery at CGMC in Linkou. The mean age of the 85 patients was years. Of these, 68 were female (mean age years) and 17 were male (mean age years). The average follow-up period for these FVPTC patients was years (control group, papillary: years; P ¼ ). The mean maximal tumor diameter was cm (range, cm) in FVPTC and cm (range cm) in the pure papillary control group. Conversely, the follicular thyroid carcinoma control group had a mean maximal diameter cm (Table 1). The lower diagnostic success rates of pre-operative FNAC and frozen sections for follicular and FVPTC groups comparing with pure papillary carcinoma group in this study were notable. Of the 85 FVPTC cases, 75 underwent preoperative FNAC examinations. Only 11 cases were diagnosed pre-operatively with papillary thyroid carcinomas. Forty-two of the 75 cases were diagnosed with follicular neoplasm and 22 cases with benign thyroid lesions. Mean tumor size of FVPTC patients was situated between that for both control groups. Surgical methods were not different for these three groups. Finally, 32.9% (follicular), 14.1% (FVPTC) and 4.1% (pure papillary) remained non-disease free at the end of Significantly more patients in the pure papillary thyroid carcinoma group presented with lymph node or soft tissue invasion than those in the follicular and FVPTC groups (34.1% versus 7.1 and 11.8%; P ¼ ). Furthermore, 29.4, 11.8 and 2.4% of follicular, FVPTC and pure papillary thyroid carcinoma patients respectively, presented with distant metastases at the time of diagnosis. The AMES risk criteria categorized 64 papillary thyroid carcinomas cases as high risk and 191 cases as low risk (Fig. 1). Of the low risk patients, 21 had pure papillary thyroid carcinomas and 20 had FVPTC and underwent subtotal thyroidectomy or lobectomy. Only one case in each group remained non-disease free. Conversely, of those in the high-risk group, seven and two with pure papillary and FVPTC, respectively, underwent these conservative procedures. Three and two patients in pure papillary thyroid carcinoma and FVPTC remained non-disease free during follow-up. Figure 2 shows the Kaplan Meier survival curves for each group. Follicular thyroid carcinoma had poorer prognosis than both papillary thyroid carcinomas groups. Of the 85 FVPTC patients, 12 were non-disease free at the time of follow-up. These 12 patients had higher postoperative Tg levels and a more advanced tumor stage at

3 690 Follicular variant of papillary thyroid carcinoma Table 1. Clinical features of follicular, follicular variant of papillary and pure papillary thyroid carcinomas FTC (n = 85) FVPTC (n = 85) Pure PTC (n = 170) P value Cytology (benign/follicular neoplasm/malignant) 21/36/10 22/42/11 23/25/ Thyroid echo (cyst/mixed/solid mass) 4/6/54 0/9/63 4/4/ Operative method (lobectomy or subtotal/nearly total thyroidectomy) 23/60 22/62 28/ Tumor size (cm) Frozen (benign/malignant) 23/35 17/48 17/ Post-operation 131 I accumulative dose (mci) Post-operation 131 I uptake (%) Post-operation thyroglobulin (ng/ml) TNM stage (stage 1/stage 2/stage 3/stage 4) 39/23/3/20 44/30/5/6 103/41/24/ AMES (low risk/high risk) 50/35 66/19 125/ Present status (disease free/non-disease free) 57/28 73/12 158/ Follow up period (years) Survival (yes/no) 70/15 82/3 163/ FTC, follicular thyroid carcinoma; FVPTC, follicular variant of papillary thyroid carcinoma; PTC, papillary thyroid carcinoma; AMES, scoring system based on age, metastases to distant sites (10); +, standard deviation. Figure 1. Analysis of papillary thyroid carcinomas in control and FVPTC patients using AMES risk criteria. In total, 64 cases were categorized as high risk and 191 were low risk. Surgical procedures were performed and follow-up status was evaluated. diagnosis, there were more of them at high risk and they received higher 131 I doses of treatment than disease free FVPTC patients (Table 2). Comparison of disease free and non-disease free cases with FVPTC showed that no significant difference existed for age, gender, tumor size diagnosed by FNAC and frozen sections, and surgical procedures. Notably, the non-disease free group had a worse prognosis (16.7% mortality) than the disease free group (Table 2). The results of comparing high- and low-risk groups with papillary thyroid carcinoma based on AMES criteria are presented in Table 3. For the FVPTC low-risk (group B) and high-risk (group D) groups, TNM stage, present status, post-operative Tg levels and survival were significantly different between the two groups. Surgical methods, tumor size and follow-up period did not differ between the two groups. Of the high-risk groups with pure papillary thyroid carcinoma

4 Jpn J Clin Oncol 2006;36(11) 691 (group C) and FVPTC (group D), group D had a higher percentage of non-disease free patients, higher post-operative Tg levels and group C had a lower survival rate (13.3% versus 10.5%). DISCUSSION FVPTC is defined as a subgroup of papillary thyroid carcinoma (7 9). Approximately 18% (42 of 227 cases) of patients with papillary thyroid carcinoma were identified as Figure 2. Kaplan Meier survival curves for the three patient groups pure papillary, FVPTC and follicular carcinoma. Table 2. Clinical features of 85 FVPTC patients in disease free and non-disease free groups FVPTC (14). Long-term follow-up studies were required to investigate the clinical features and treatment outcomes for FVPTC. In this study, the clinical characteristic of FVPTC was similar to that of follicular thyroid cancer. Clinical and laboratory analyses indicated the existence of separate mechanisms and routes for distant metastasis and either extrathyroidal growth or lymph node metastasis of thyroid cancer. A high ratio of papillary thyroid cancer had extra-thyroidal growth or lymph node metastasis. Conversely, follicular thyroid cancer exhibited a more distant metastases than papillary thyroid cancer (4, 5). As in this investigation, FVPTC patients had a better survival rate than follicular thyroid cancer and fewer cases with lymph-node or softtissue invasions than pure papillary thyroid cancer control patients. Pre-operative diagnosis for FVPTC has recently been investigated (15 17). The diagnostic features of FNAC are thick eosinophilic colloid balls in the background, multilayered microfollicles (rosettes), numerous grooves and inclusions in follicular cell monolayers. All cytological analyses of FVPTC, including those by Goodell et al. from the US (15), Nair et al. from India (17), Fulciniti et al. from Italy (18) and Kumar et al. from Iran (16) are retrospective studies with small series that attempted to identify the cytopathological correlation between FVPTC and other thyroid malignancies. This investigation showed a lower preoperative diagnostic rate for FVPTC compared with that for pure papillary thyroid carcinoma in these previous reports (19). In this study, over one-quarter of FVPTC cases (17/65) were not diagnosed by frozen section. A recent study indicated that frozen section has a low diagnostic sensitivity (25 42%) for diagnosing follicular thyroid carcinoma (20). Disease free (n = 73) Non-disease free (n = 12) P value Age (years) Gender (female/male) 61/12 7/ Tumor size (cm) Cytology (benign/follicular neoplasm/malignant) 18/38/10 4/4/ Thyroid function (euthyroid/hyperthyroidism) 69/3 11/ Pre-operative echo (mixed/solid mass) 8/55 1/ Operative method (lobectomy or subtotal/nearly total thyroidectomy) 19/54 3/ Frozen (benign/malignant) 19/39 2/ I accumulative dose (mci) Post-operation thyroglobulin (ng/ml) TNM stage (stage 1/stage 2/stage 3/stage 4) 41/27/5/0 3/3/0/ AMES (low risk/high risk) 64/9 2/ Follow-up (year) Survival (yes/no) 72/1 10/ FVPTC, follicular variant of papillary thyroid carcinoma; AMES, scoring system based on age, metastases to distant sites (10); +, standard deviation.

5 692 Follicular variant of papillary thyroid carcinoma Table 3. Clinical features of patients with pure papillary and FVPTC in high- and low-risk groups Group A AMES low risk, Control (n = 125) The extent of surgical treatment for thyroid carcinoma, including that for FVPTC, is dependent on patient prognosis. In this investigation, AMES criteria were applied retrospectively to assess patient prognosis. Comparison of high- and low-risk groups for pure papillary and FVPTC showed that pure papillary and FVPTC cases in the high-risk group received less aggressive surgical procedures, resulting in a higher ratio of non-disease free patients. We agree with the principle that pure papillary and FVPTC patients can be treated with the same surgical methods (7, 8). Total thyroidectomy with lymph node dissection is indicated for all high-risk papillary thyroid carcinomas. Compared with pure papillary thyroid carcinoma, difficulties in pre-operative diagnosis and high ratios of initial clinical presentation with distant metastases were the main problems to be overcome (21). In summary, most FVPTC cases were diagnosed as follicular neoplasms with pre-operative FNAC, a higher ratio of benign cytological findings compared with that for the control group with pure papillary thyroid cancer. FVPTC had a substantially higher ratio of distant metastases with less lymph node metastases and soft tissue invasion noted during surgery than pure papillary thyroid carcinoma group. The clinical behavior of FVPTC can be regarded as located between that of pure papillary and follicular thyroid carcinomas. After aggressive treatment, prognosis for FVPTC does not differ from that for pure papillary thyroid carcinoma. Group B AMES low risk, FVPTC (n = 66) References Group C AMES high risk, Control (n = 45) Group D AMES high risk, FVPTC (n = 19) Age (years) P. 0.05* Pre-op cytology (benign/follicular neoplasm/malignant Operation method (lob+subt/nearly total thyroidectomy) P value 17/18/3 19/32/9 6/7/25 3/10/ /102 20/46 7/37 2/ Tumor size (cm) a,b,c Frozen section (benign/malignant) 14/81 15/35 3/33 2/ TNM stage (stage 1/stage 2/stage 3/stage 4) 85/35/5/0 40/23/3/0 18/6/19/2 4/7/2/ Present status (disease free/non-disease free) 121/4 64/2 37/8 9/ Post-op 131 I accumulative dose (mci) b,c,d,e Post-op 131 I uptake (%) P. 0.05* Post-op 1 month Tg (ng/ml) c,e,f Follow up period (years) a,d Survival (yes/no) 124/1 65/1 39/6 17/ a, Group A versus Group B, P, 0.005; b, Group A versus Group C, P, 0.005; c, Group A versus Group D, P, 0.005; d, Group B versus Group C, P, 0.005; e, Group B versus Group D, P, 0.005; f, Group C versus Group D, P, P. 0.05*, no statistically significant difference among four groups. FVPTC, follicular variant of papillary thyroid carcinoma; AMES, scoring system based on age, metastases to distant sites (10); +, standard deviation; op, operation; lob, lobectomy; subt, subtotal thyroidectomy; Tg, thyroglobulin. 1. Reynolds RM, Weir J, Stockton DL, Brewster DH, Sandeep TC, Strachan MW. Changing trends in incidence and mortality of thyroid cancer in Scotland. Clin Endocrinol 2005;62: Leenhardt L, Grosclaude P, Cherie-Challine L; Thyroid Cancer Committee. Increased incidence of thyroid carcinoma in France: a true epidemic or thyroid nodule management effects? Report from the French Thyroid Cancer Committee. Thyroid 2004;14: Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L, et al. A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 2003;88: Schelfhout LJ, Creutzberg CL, Hamming JF, Fleuren GJ, Smeenk D, Hermans J, et al. Multivariate analysis of survival in differentiated thyroid cancer: the prognostic significance of the age factor. Eur J Cancer 1988;24: Samaan NA, Schultz PN, Hickey RC, Goepfert H, Haynie TP, Johnston DA, et al. The results of various modalities of treatment of well differentiated thyroid carcinoma: a retrospective review of 1599 patients. J Clin Endocrinol Metab 1992;75: Chen KT, Rosai J. Follicular variant of thyroid papillary carcinoma: a clinicopathologic study of six cases. Am J Surg Pathol 1977;2: Zidan J, Karen D, Stein M, Rosenblatt E, Basher W, Kuten A. Pure versus follicular variant of papillary thyroid carcinoma: clinical features, prognostic factors, treatment, and survival. Cancer 2003;97: Passler C, Prager G, Scheuba C, Niederle BE, Kaserer K, Zettinig G, et al. Follicular variant of papillary thyroid carcinoma: a long-term follow-up. Arch Surg 2003;138: Wittekind Ch, Wagner G, editors. UICC TNM Klassifikation maligner Tumore. 5th edn. Berlin: Springer; 1997.

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