Tumor Size Is Still a Useful Prognostic Factor for the Therapeutic Plan of Papillary Thyroid Carcinoma

A R TIC LE Vol. 4, No. 1, May 2011

Received March 7, 2011 / Accepted April 14, 2011

Correspondence: Jae Hoon Chung, MD, PhD, Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea

Tel: 82-2-3410-3434, Fax: 82-2-3410-6956, E-mail: thyroid@skku.edu

*Address all correspondence and requests for reprints to: Dr. Jae Hoon Chung, MD, PhD, Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Tae Sik Jung, MD, PhD and Jung Hwa Jung, MD, PhD are currently working in Division of Endocrinology and Metabolism, Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea

Hee Kyung Kim, MD is currently working in Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Korea Hyun Won Shin, MD is currently working in Division of Endocrinology and Metabolism, Department of Internal Medicine, Gimpo Woori Hospital, Gimpo, Korea

Tumor Size Is Still a Useful Prognostic Factor for the Therapeutic Plan of Papillary Thyroid Carcinoma

Tae Sik Jung, MD, PhD, Hee Kyung Kim, MD, Hyun Won Shin, MD, Jung Hwa Jung, MD, PhD, Hye Won Jang, MD, PhD, Sun Wook Kim, MD, PhD, Man Ki Chung, MD, PhD ² , Jung Han Kim, MD, PhD ¹ , Jee Soo Kim, MD, PhD ¹ , Young-Ik Son, MD, PhD ² and Jae Hoon Chung, MD, PhD

Division of Endocrinology and Metabolism, Departments of Medicine; Surgery

; Otorhinolaryngology-Head & Neck Surgery

, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Background and Objectives: Papillary thyroid microcarcinoma (PTMC) was regarded as early-stage carcinoma, but its aggressiveness has been frequently reported. We performed this study to compare the clinicopathologic characteristics of PTMC with those of papillary thyroid carcinoma (PTC) ＞1 cm. We evaluated the association of clinicopathologic parameters of PTMC with tumor size divided by each millimeter. Materials and Methods:

We retrospectively analyzed the medical records of 1,139 patients with PTMC and 1,296 patients with PTC ＞1 cm who underwent thyroidectomy from 1995 to 2004 at Samsung Medical Center. The aggressive variants of PTC were excluded in the subjects. Results: Multifocality, extrathyroidal invasion (ETI), lymph node invasion (LNI), and distant metastasis (DM) were significantly less frequent in PTMC than PTC ＞ 1 cm (p ＜ 0.001). Recurrence and disease-specific mortality rates for PTMC were also significantly lower than those of PTC ＞1 cm (recurrence 2.9% vs. 8.1%, p＜0.001; mortality 0.5 % vs. 1.5%, p＜0.05). Tumor size was correlated with the rates of multifocality, ETI, LNI, and DM in all PTC (p ＜ 0.01). All patients with DM had the tumor size 0.6 cm in diameter or more. Among PTMC, the rates of LNI, multifocality, and N1b significantly increased when tumor size exceeded 0.3 cm, 0.4 cm, and 0.6 cm, respectively (p ＜ 0.05). Conclusion: Recurrence and mortality rates of PTMC were extremely low, although local invasion was detected on the level of subcentimeter. Tumor size was well correlated with the aggressiveness of PTC. We suggest that tumor size is still a useful prognostic factor for the therapeutic plan of PTC.

Key Words: Thyroid neoplasm, Carcinoma, Papillary, Recurrence, Mortality

Introduction

There is a linear relationship between tumor size

and cancer recurrence and mortality for differentiated thyroid carcinoma.

Tumor size is an important prognostic factor for evaluation of thyroid carcinoma.

Papillary thyroid microcarcinoma (PTMC) is defined as

PTMC (n=1,139)

PTC ＞1 cm (n=1,296) p value

Size (cm) 0.65±0.23

(0.1∼1.0)

2.22±1.23 (1.1∼14.0)

＜0.001

Age (years) 46.3±11.1

(14∼80)

44.9±13.3 (9∼81)

＜0.001

Gender (male：female) 115：1,024 198：1,098 ＜0.001 Total thyroidectomy 937 (82%) 1,266 (95%) ＜0.001 Lymph node dissection 619 (54%) 956 (74%) ＜0.001 Radioiodine therapy 890 (78%) 1,219 (94%) ＜0.001 Multifocality 330 (29%) 446 (34%) ＜0.001 Bilaterality 227 (20%) 346 (27%) ＜0.001 Extrathyroidal invasion 498 (44%) 887 (68%) ＜0.001 Lymph node invasion 267 (23%) 661 (51%) ＜0.001

N1a 175 381 ＜0.001

N1b 92 280 ＜0.001

Distant metastasis 8 (0.7%) 42 (3.2%) ＜0.001 TNM stage

Stage I 805 (71%) 712 (55%) ＜0.001 Stage II 3 (0.3%) 59 (4.6%) ＜0.001 Stage III 282 (25%) 376 (29%) ＜0.05 Stage IV 49 (4.3%) 149 (12%) ＜0.001 Recurrence rate 26 (2.9%) 105 (8.1%) ＜0.001 Disease-specific

mortality rate

6 (0.5%) 20 (1.5%) ＜0.05

PTC: papillary thyroid carcinoma, PTMC: papillary thyroid microcarcinoma

Table 1. Comparison of clinicopathologic characteristics of PTMC with those of PTC ＞1 cm in diameter

being 1 cm in diameter or less. Kasai and Sakamoto divided small thyroid carcinoma of 1 cm and less in diameter into two subgroups: tiny carcinoma (＞0.5 cm) and minute carcinoma (≤0.5 cm). They sug- gested that the risk of lymph node metastasis increased, but the metastasis was limited to the perithyroidal and peritracheal area when the tumor diameter exceeded 0.5 cm.

In the previous reports, twenty to forty-seven per- cents of patients with PTMC had multifocal tumors, 15

∼20% had extrathyroidal invasion and 13∼64% had cervical lymph node invasion.

However, the rate of distant metastasis has been reported to be very low (0∼1.6%).

The recurrence and cancer-specific mortality rates of PTMC have been reported to be extremely low: recurrence rate 0∼10%, mortality rate 0∼1.3%.

There have been no reports on the association of clinicopathologic parameters of PTMC with variable tumor size when the tumor was divided by each millimeter. Therefore, we performed this study to analyze the association of clinicopathologic para- meters of PTMC with tumor size divided by each millimeter. We also compared the clinicopathologic characteristics of PTMC with those of papillary thyroid carcinoma (PTC) more than 1 cm in diameter (PTC ＞ 1 cm).

Materials and Methods

We retrospectively analyzed the medical records of 2,435 patients with PTC underwent thyroidectomy from 1995 to 2004 at Samsung Medical Center in Korea. Follicular variants and encapsulated variants of PTC as well as classical PTC were included, but the aggressive variants such as tall cell variants, columnar cell variants, and diffuse sclerosing variants of PTC were excluded in the subjects. Follicular variants and encapsulated variants of PTC were detected in 27 patients with PTMC (2.4%) and 64 patients with PTC

＞1 cm (4.9%), respectively. Among 2,435 patients with PTC, 1,139 patients (47%) had PTMC and the other 1,296 patients (53%) had PTC ＞1 cm. The mean diameter of PTMC was 0.65±0.23 cm (mean±

SD, range 0.1∼1.0 cm), whereas that of PTC ＞1 cm was 2.22±1.23 cm (1.1∼14.0 cm). Mean age of patients was 46.3±11.1 years (14∼80 years) in PTMC, and 44.9±13.3 years (9∼81 years) in PTC

＞1 cm. Male proportion was 10% (n=115) in PTMC, and 15% (n=198) in PTC ＞1 cm. Total thyroidectomy was done in 937 patients with PTMC (82%) and 1,226 patients with PTC ＞1 cm (95%), respectively.

Remaining patients underwent subtotal thyroidectomy or lobectomy. Cervical or mediastinal lymph node dissection was done simultaneously with thyroidec- tomy in 619 patients with PTMC (54%) and 956 patients with PTC ＞1 cm (74%), respectively. Surgical extent was determined according to the surgeon’s experience and disease extent. Eight hundred ninety patients with PTMC (78%) and 1,219 patients with PTC

＞1 cm (94%) underwent radioactive iodine (RAI) therapy after thyroidectomy, respectively (Table 1).

The mean follow-up period was 85±24 months

χ

p value

Multifocality 6.59 0.01

Bilaterality 14.64 ＜0.001

Extrathyroidal invasion 154.88 ＜0.001

Lymph node invasion 223.35 ＜0.001

N1a 38.10 ＜0.001

N1b 168.25 ＜0.001

Distant metastasis 51.46 ＜0.001

Total thyroidectomy 76.22 ＜0.001

Lymph node dissection 81.11 ＜0.001

Radioiodine therapy 95.05 ＜0.001

PTC: papillary thyroid carcinoma. All PTC was divided into nine groups according to the tumor size divided by each 0.5 cm interval, and compared the rates of clinicopathologic parameters; 0.1∼0.5 cm (n=397), 0.6∼1.0 cm (n=742), 1.1

∼1.5 cm (n=346), 1.6∼2.0 cm (n=310), 2.1∼2.5 cm (n=226), 2.6∼3.0 cm (n=126), 3.1∼3.5 cm (n=118), 3.6∼

4.0 cm (n=44), more than 4.1 cm (n=126)

Table 2. The clinicopathologic parameters correlated with tumor size in PTC

(52∼172 months) for patients with PTMC, whereas 94±31 months (47∼179 months) for patients with PTC ＞1 cm. Most of PTMC was detected by ultra- sonography performed during health check-up, but some (less than 1%) were discovered during or after thyroidectomy for benign thyroid diseases.

Tumor staging was evaluated using the pTNM staging system established by the American Joint Committee on Cancer (AJCC) 2002.

We defined the lymph node invasion as histologic confirmation of the tumor, but some mediastinal lymph node invasions as its presence detected by RAI whole body scan. We also defined the distant metastasis as histologic confirmation of the tumor or the presence of typical features detected by radiological studies, RAI whole body scan or PET scan. The Institutional Review Board at Samsung Medical Center approved the study protocol.

When we compared the clinicopathologic para- meters of PTMC with those of PTC ＞1 cm, extent of surgery, RAI therapy, multifocality, bilaterality, the presence of lymph node or extrathyroidal invasion, the presence of the distant metastasis, and TNM staging were analyzed by Pearson’s chi square test. Fisher’s exact test was used when the expected frequency was less than five. The association of clinicopathologic parameters with the increment of tumor size was evaluated by linear by linear association. p values less than 0.05 were considered significant. Values were expressed as mean±SD.

Results

Comparison of clinicopathologic characteristics of PTMC with PTC ＞1 cm (Table 1)

Multifocal tumor was found in 330 patients with PTMC (29%) and 446 patients with PTC ＞1 cm (34%), respectively (p＜0.001). Two hundred twenty- seven patients with PTMC (20%) had tumor foci in both lobes, whereas 346 patients with PTC ＞1 cm (27%) had tumor foci in both lobes (p＜0.001).

Pathology revealed that 498 patients with PTMC (44%) and 887 patients with PTC ＞1 cm (68%) had extrathyroidal invasion, respectively (p＜0.001).

Lymph node invasion was detected in 267 patients with PTMC (23%) and 661 patients with PTC ＞1 cm (51%), respectively (p＜0.001). Among 267 PTMC patients with lymph node invasion, 175 patients (66%) had N1a disease, and 92 patients (34%) had N1b disease. Three hundred eighty-one of 661 patients (58%) with PTC ＞1 cm had N1a disease, and the other 280 patients (42%) had N1b disease. Distant metastasis was detected in eight patients with PTMC (0.7%) and 42 patients with PTC ＞1 cm (3.2%) (p＜

0.001). Among 50 PTC patients with distant meta- stasis, tumors were metastasized only to the lung in 54%, only to the bone in 30%, to the lung & bone in 12%, and to multiple organs in 4%.

According to TNM staging system, the patients with PTMC were more prevalent in stage I disease than those with PTC ＞1 cm (71% vs. 55%, p＜0.001).

However, the patients with PTMC were less prevalent in stage II, III, and IV diseases than those with PTC ＞1 cm, respectively (stage II 0.3% vs. 4.6%, p＜0.001;

stage III 25% vs. 29%, p＜0.05; stage IV 4.3% vs.

12%, p＜0.001).

Recurrence rate of PTMC was significantly lower than that of PTC ＞1 cm (2.9% vs. 8.1%, p＜0.001).

Disease-specific mortality rate of PTMC was also

significantly lower than that of PTC ＞1 cm (0.5% vs.

Fig. 1. Cutoff values of tumor size affecting aggressiveness of papillary thyroid microcarcinoma. 1) Lymph node invasion, bilaterality and TNM stage III & IV; black bar was the frequency of 1∼2 mm sized tumor and grey bar was the frequency of 3∼10 mm sized tumor, 2) multifocality; black bar was the frequency of 1∼3 mm sized tumor and grey bar was the frequency of 4∼10 mm sized tumor, 3) N1b; black bar was the frequency of 1∼5 mm sized tumor and grey bar was the frequency of 6∼10 mm sized tumor, *p＜0.005,

p

＜0.05.

1.5%, p＜0.05).

Analysis of tumor size affecting the clinico- pathologic parameters in all PTC (Table 2)

We analyzed tumor size affecting the clinico- pathologic parameters in 2,435 patients with all PTC including PTMC. They were divided into nine groups according to the tumor size divided by each 0.5 cm interval, and compared the rates of clinicopathologic parameters; 0.1∼0.5 cm (n=397), 0.6∼1.0 cm (n=

742), 1.1∼1.5 cm (n=346), 1.6∼2.0 cm (n=310), 2.1

∼2.5 cm (n=226), 2.6∼3.0 cm (n=126), 3.1∼3.5 cm (n=118), 3.6∼4.0 cm (n=44), more than 4.1 cm (n=

126).

Tumor size was correlated with the rates of multifocality (χ

=6.59, p=0.01), bilaterality (χ

=14.64, p＜0.001), extrathyroidal invasion (χ

=154.88, p＜

0.001), lymph node invasion (χ

=223.35, p＜0.001), stage N1a (χ

=38.10, p＜0.001), stage N1b (χ

= 168.25, p＜0.001), and distant metastasis (χ

=51.46, p＜0.001). Tumor size was also correlated with the rates of total thyroidectomy (χ

=76.22, p＜0.001),

lymph node dissection (χ

=81.11, p＜0.001), and RAI therapy (χ

=95.05, p＜0.001).

Determination of tumor size affecting clinico- pathologic parameters in PTMC (Fig. 1)

We determined tumor size affecting the clinico- pathologic parameters in 1,139 patients with PTMC.

They were divided into two groups according to the tumor size by each 0.1 cm interval, and compared the rates of clinicopathologic parameters; 0.1 cm group (n=14) vs. 0.2∼1.0 cm group (n=1,125), 0.1∼0.2 cm group (n=47) vs. 0.3∼1.0 cm group (n=1,092), 0.1∼

0.3 cm group (n=138) vs. 0.4∼1.0 cm group (n=

1,001), 0.1∼0.4 cm group (n=231) vs. 0.5∼1.0 cm group (n=908), 0.1∼0.5 cm group (n=397) vs. 0.6∼

1.0 cm group (n=742), 0.1∼0.6 cm group (n=563) vs. 0.7∼1.0 cm group (n=576), 0.1∼0.7 cm group (n=713) vs. 0.8∼1.0 cm group (n=426), 0.1∼0.8 cm group (n=888) vs. 0.9∼1.0 cm group (n=251), 0.1∼

0.9 cm group (n=960) vs. 1.0 cm group (n=179).

The rate of extrathyroidal invasion was correlated with the increment of tumor size. The rates of bilaterality and lymph node invasion significantly increased when tumor size exceeded 0.3 cm (p

＜0.05). The rate of multifocality significantly increased when tumor size exceeded 0.4 cm (p＜0.005). The rate of N1a was not associated with tumor size, but the rate of N1b significantly increased when tumor size exceeded 0.6 cm (p＜0.005). The rate of distant metastasis was not associated with tumor size, but all patients with distant metastasis had PTMC more than 0.6 cm. The rates of TNM stage III and IV significantly increased when tumor size exceeded 0.3 cm (p＜

0.005).

Discussion (Table 3)

This study confirmed that recurrence and disease-

specific mortality rates in patients with PTMC were

extremely low, although local invasion was detected

on the level of subcentimeter. Initial pathologic para-

meters (multifocality, bilaterality, lymph node invasion,

and extrathyroidal invasion) in the patients with PTMC

were less aggressive than those in the patients with

Author Jung Roti Pellegriti Chow Wada Yamashita Baudin Noguchi Hay

Year 2011 2006 2004 2003 2003 1999 1998 1996 1992

Reference number - [18] [17] [13] [15] [16] [6] [11] [3]

Country Korea Italy Italy China Japan Japan France Japan USA

Number 1,139 243 299* 203 259 1,743

281 867

535

Mean age (years) 46 52 42 47 48 46 42 43 45

Mean follow-up (years) 7.1 4.4 3.8

8.4 5.1 11.2 7.3 12.8 17.5

Multifocality (%) 29 32 32 31 25 40 20

Bilaterality (%) 20 19 18 - 10 16 10

Extrathyroidal invasion (%) 44 17 20 21 15 2

Lymph node invasion (%) 23 13 30 25 64 43 8.7 32

Distant metastasis (%) 0.7 1.6 2.7 2.5 0 2.8 0.2

Total thyroidectomy (%) 82 100 95 92 11 69 0.3

74

Lymph node dissection (%) 54 97 - 27 100 19 69 13 44

RAI therapy (%) 78 96 45 68 44 10

Recurrence rate (%) 2.9 1.7 26** 10 2.3 1.8 3.9 1.4 6

Mortality rate (%) 0.5 1.0 0 1.0 0 0.2 0 0.2 0.4 RAI: radioactive iodine, *tumors smaller than 1.5 cm and including 34 patients with FMTC,

including 82 patients with other thyroid microcarcinomas,

including other thyroid microcarcinomas,

median follow-up,

The surgeon reported that the tumor had invaded adjacent extrathyroidal structures,

Most of them were diagnosed as carcinoma after thyroidectomy, **relapse/

persistent during follow-up,

twenty-year tumor recurrence rate

Table 3. Comparison of clinicopathologic characteristics of PTMC reported in the previous literatures.

PTC ＞1 cm, but their rates were not low than expected. The rates of multifocality, bilaterality and lymph node invasion in PTMC were from 20 to 29%, and the rate of extrathyroidal invasion reached to 44%, but the rate of distant metastasis was extremely low (0.7%). Although prognosis of PTMC was known to be more favorable than that of PTC ＞1 cm, pathologic factors suggesting aggressiveness such as multifo- cality and lymph node invasion were reported to be highly prevalent in PTMC.

Cervical lymph node invasion and recurrence rate were also reported to be high in patients with multifocal PTMC (lymph node invasion 25~43%, recurrence 3.9~10%).

Large-scale comparative study of clinicopathologic characteristics of PTMC with PTC ＞1 cm has not been performed. Chow et al. reported that multifocality of 203 patients with PTMC was not different (31% vs.

31%), but the frequencies of extrathyroidal extension (21% vs. 47%, p＜0.001), cervical lymph node meta- stasis (25% vs. 33%, p＜0.05), distant metastasis (1%

vs. 4%, p＜0.05), and 10-year survival rate (100% vs.

92%, p＜0.01) were significantly different from PTC ＞ 1 cm.

Rodriguez et al. also found significant diffe- rences in the incidence of adenopathy (17% vs. 37%, p＜0.05), mortality (0% vs. 11%, p＜0.05), and TNM

stage (stage I, 97% vs. 53%, p＜0.001; stage II, 0%

vs. 16%, p＜0.01; stage III, 3% vs. 20%, p＜0.01) between 36 PTMC and 122 PTC ＞1 cm.

In this study, we retrospectively reviewed the medical records of 2,435 patients with PTC underwent thyroi- dectomy between 1994 and 2005 at a single hospital.

Among 2,435 patients with PTC, 1,139 patients (47%) had PTMC and the other 1,296 patients (53%) had conventional PTC. We compared the clinicopathologic parameters of PTMC with those of PTC ＞1 cm. The aggressiveness expressed as multifocality, bilaterality, extrathyroidal invasion, lymph node invasion, and distant metastasis was significantly less remarkable in PTMC than PTC ＞1 cm. The patients with PTMC were more prevalent in stage I disease, but the patients with PTC ＞1 cm were more prevalent in stage II, III and IV diseases (Table 1).

In this study, tumor size was correlated with the

rates of multifocality, bilaterality, extrathyroidal invasion,

lymph node invasion, and distant metastasis. In addi-

tion, it was also correlated with the rates of total

thyroidectomy, lymph node dissection, and RAI the-

rapy (Table 2). Many investigators have reported that

clinical features were correlated with tumor size in

PTMC. Chow et al. reported that PTMC with 0.5 cm

or smaller in diameter had lower frequency of extrathyroidal extension than PTMC more than 0.5 cm (4.3% vs. 29.3%, p＜0.001), but other clinical features were not different between both of subgroups. They concluded that the subdivision of PTMC according to the size (≤0.5 cm vs. ＞0.5 cm) did not have a significant impact on the patient outcome.

Wada et al. compared the lymph node invasion between PTMC with 0.5 cm or smaller and PTMC more than 0.5 cm.

PTMC with 0.5 cm or smaller had lower frequency of overall node invasion (55.7% vs. 73.7%, p＜0.05), central node invasion (50.8% vs. 68.2%, p＜0.05), and lateral node invasion (21.3% vs. 40.4%, p＜0.01) than PTMC more than 0.5 cm.

Ito et al. evaluated the cervical lymph node invasion of 600 patients with PTMC, and they divided the patients into two groups according to the tumor size 0.7 cm. PTMC smaller than 0.7 cm had lower frequency of cervical lymph node invasion than PTMC 0.7 cm or more (42.5% vs.

53.5%, p＜0.05). They also reported that lateral cer- vical node invasion proven by lateral neck dissection was less detected in PTMC smaller than 0.7 cm than PTMC 0.7 cm or more (34.5% vs. 47.7%, p＜0.05).

From these results, the rates of extrathyroidal exten- sion or cervical lymph node invasion seemed to be increased when tumor size exceeded 0.5 or 0.7 cm.

However, many investigators reported that other cli- nicopathologic parameters such as multifocality, bila- terality and distant metastasis were not correlated with tumor size in PTMC. In this study, we revealed that the rates of multifocality, bilaterality, cervical lymph node invasion, and TNM stage III or IV significantly increased when tumor size exceeded 0.3∼0.4 cm, and the rates of lateral or mediastinal lymph node invasion significantly increased when tumor size exceeded 0.6 cm (Fig. 1). The rate of extrathyroidal extension was also correlated with the increment of tumor size. In addition, 705 patients (62%) with PTMC had at least one factor suggesting aggressiveness: multifocality, extrathyroidal extension, lymph node invasion, and distant metastasis. Therefore, total or near-total thyroi- dectomy with central neck dissection had better to be considered in patients with PTMC more than 0.3∼0.4 cm, and lateral neck dissection should be considered

in PTMC more than 0.6 cm. Many investigators re- ported that distant metastasis was detected in PTMC more than 0.8 cm, and its prevalence at the time of presentation was 2.5%.

In this study, detection rate of distant metastasis at the time of diagnosis was significantly lower in PTMC than PTC ＞1 cm (0.7%

vs. 3.2%, p＜0.001). All PTMC patients with distant metastasis had the tumor size 0.6 cm in diameter or more.

From these results, we could draw the conclusions that the tumor aggressiveness expressed as multi- focality, bilaterality, extrathyroidal invasion, lymph node invasion, and distant metastasis was increased in PTMC according to increment of the tumor size, although the recurrence and disease-specific mor- tality rates were extremely low. Because the clini- copathologic characteristics of PTMC were changed according to the tumor size, extent of surgery in- cluding neck dissection should be considered depen- dent on its size.

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