Clinical Study of Papillary Thyroid Carcinoma | SciTechnol

Watanabe and Suzuki, J Otol Rhinol 2015, 4:1 http://dx.doi.org/10.4172/2324-8785.1000209

Journal of Otology & Rhinology

Research Article

A SCITECHNOL JOURNAL

Clinical Study of Papillary Thyroid Carcinoma Tetsuo Watanabe* and Masashi Suzuki Department of Otolaryngology, Oita University Faculty of Medicine, 1-1 Idaigoka, Hasama-machi, Yufu city, Oita 879-5593, Japan *Corresponding

author: Tetsuo Watanabe, MD, PhD, Department of Otolaryngology, Oita University Faculty of Medicine, 1-1, Idaigoka, Yufu-city, Oita 879-5593, Japan, Tel: 81-97-586-5913; Fax: 81-97-549-0762; E-mail address:

[email protected] Rec date: May 20, 2014 Acc date: Nov 24, 2014 Pub date: Jan 27, 2015

Abstract Objective: The purpose of this study was to summarize the treatment outcomes of thyroid carcinoma at our hospital in order to develop future treatment strategies. Methods: A total of 86 patients with papillary thyroid carcinoma (PTC) who underwent primary surgical treatment between 1988 and 2007 were analyzed. The patients included 24 males and 64 females between 19 and 83 years of age (median age: 60.1 years). We evaluated the clinical stage using the 6th edition of the American Joint Committee on Cancer (AJCC)/ International Union Against Cancer (UICC) tumor-nodemetastasis (TNM) classification. The disease-specific survival rate was calculated according to the Kaplan-Meier method, and differences between the stages were compared according to the log-rank test. Cox multivariate regression analysis was used to evaluate the treatment outcomes. Results: Recurrence occurred in 20 (23.2%) patients. The 10year disease specific survival rate among all patients was 89.0%. The pT stage and the post-operative TNM stage had a tendency to reduce survival. Conclusions: The TNM staging classification is an appropriate staging system for predicting the prognosis. Although most of the patients evaluated in this study had an excellent prognosis, countermeasures against recurrences in the cervical lymph nodes were required.

Keywords: Papillary thyroid carcinoma; AJCC/UICC TNM; Cervical lymph node

to the prolonged natural history of the disease in most patients and the lack of good level 1 or 2 evidence from prospective trials. Most recommendations and guidelines are based on large, retrospective analyses and expert consensus opinion. The purpose of this study was to summarize the treatment outcomes of thyroid carcinoma at our hospital in order to develop future treatment strategies.

Subjects and Methods This study was approved by the Ethical Committee of Oita University Faculty of Medicine and was retrospective study performed using a review of the patients’ medical charts. Ninety-seven patients underwent primary surgical treatment for thyroid carcinoma at this hospital between 1988 and 2007. Patients with distant metastases found prior to the initiation of therapy were excluded. Eighty-six patients had papillary carcinoma, four patients had follicular carcinoma, four patients had medullary carcinoma, two patients had squamous cell carcinoma and one patient had undifferentiated carcinoma. We reviewed the records of the 86 patients with papillary thyroid carcinoma (PTC). The patients consisted of 24 males and 64 females between 19 and 83 years of age (mean age: 60.1 years). PTC was found incidentally during surgery for benign disease, laryngeal carcinoma, hypopharyngeal carcinoma or parathyroid gland carcinoma in 15 patients. In 14 patients, PTC was found in the form of regional lymph node metastasis originating from an occult primary source. No primary lesions were found in three of these 14 patients. Thyroid-stimulating hormone (TSH) suppression therapy was administered in all of the patients with PTC. We evaluated the clinical stage using the 6th edition of the American Joint Committee on Cancer (AJCC)/International Union against Cancer (UICC) tumor-nodemetastasis (TNM) classification. The 10 year disease-specific survival rate was calculated according to the Kaplan-Meier method, and differences between the stages were compared using the log-rank test. The median follow-up period was 101 months (range: 2-281 months). Cox multivariate regression analysis for disease-specific survival outcomes was conducted with the predictor variables: age, sex (male: 0, female: 1), pT stage (0, 1: 0, 2,3: 1, 4: 2), pN stage ( 0: 0, 1a: 1, 1b: 2) and postoperative TNM stage (I, II, III: 0, IV: 1). The calculations were made using the Excel Statistics software package (Social Survey Research Information Co. Ltd, Tokyo). A P value of less than 0.05 was considered to be statistically significant.

Results

Introduction In recent years, many clinical practice guidelines have been developed and become popular as routine clinical norms. With respect to thyroid carcinoma, the American Thyroid Association (ATA) published guidelines for patients with thyroid nodules and welldifferentiated thyroid cancer in 1996 [1]. In 2006, the European Thyroid Association (ETA) published guidelines for patients with differentiated thyroid carcinoma of the follicular epithelium [2]. In Japan, thyroid tumor management guidelines were issued by the Japan Association of Endocrine Surgeons and the Japanese Society of Thyroid Surgery in 2010. However, the management of welldifferentiated thyroid carcinoma remains controversial, primarily due

Patients with recurrence Overall, local and distant recurrence occurred in 15 (17.4%) and 5 (5.8%) patients, respectively. Local recurrence occurred in the thyroid gland in five patients and in the neck lymph node in 10 patients. Detailed information regarding the 20 patients with recurrence is presented in Table 1. Five patients developed local recurrence in the thyroid gland. Two of these cases involved stage I disease, and salvage surgery was successful in both cases.

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Citation:

Watanabe T, Suzuki M (2015) Clinical Study of Papillary Thyroid Carcinoma. J Otol Rhinol 4:1.

doi:http://dx.doi.org/10.4172/2324-8785.1000209 Ten patients developed local recurrence in the neck lymph nodes. Salvage surgery was successfully performed in one patient with stage III disease. The other nine patients had pN1b, stage IVA disease. Only two of these patients were treated successfully with salvage surgery. Five patients developed distant recurrence. Salvage treatment was unsuccessful in all of these cases.

Disease-specific survival rate Three patients died from diseases other than thyroid carcinoma. The 10-year disease-specific survival rate among all patients was 89.0%.

T classification of the subjects The pre- and postoperative T stages are shown in Table 2. Table 3 presents the T stages and extent of resection of the thyroid gland. The lower line in each cell of the tables indicates the number of patients who developed recurrence. Figure 1 shows the overall survival rate according to the T classification.

Figure 2: N classification and prognosis.

TNM stages of the subjects The pre- and postoperative TNM stages are shown in Table 6. The lower line in each cell of the table indicates the number of patients who developed recurrence. Figure 3 shows the overall survival rate according to the TNM classification.

Figure 1: T classification and prognosis. The preoperative T stage was not consistent with the pT stages in 42 of the 86 patients (48.8%). The number of episodes of recurrence increased in association with progression of the pT stage.

N classification of the subjects The pre- and postoperative N stages are shown in Table 4. Table 5 shows the N stages and extent of neck dissection. The lower line in each cell of the tables indicates the number of patients who developed recurrence. Figure 2 shows the overall survival rate according to the N classification. The preoperative N stage was not consistent with the pN stage in 31 of the 86 patients (36.0%). Although the number of episodes of recurrence increased in association with progression of the pN stage, there were no statistically significant differences in the pN stage.

Figure 3: TNM stage classification and prognosis. The preoperative TNM stage was not consistent with the pTNM stage in 23 of the 86 patients (26.7%). The number of episodes of recurrence increased in association with progression of the postoperative TNM stage.

Cox multivariate regression analysis The results of the Cox multivariate regression analysis are shown in Table 7. No patient variables have a significant impact on survival. However, the advanced pT stage and the advanced postoperative TNM stage had a tendency to reduce survival.

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doi:http://dx.doi.org/10.4172/2324-8785.1000209

Age

Sex

Site of recurrence

pT

pN

Stage

Extent of resection of thyroid gland

Extent of

pEx

neck dissection

39

F

Local (thyroid gland)

4a

1b

I

Lobectomy

Ipsilateral IVI

2

*

52

F


1a

0

I

Lobectomy

none

0

*

68

F


1b

1b

IVA

Tyroidectomy

Ipsilateral IVI

2

71

F


4a

0

IVA

Tyroidectomy

VI

2

73

F


4a

1b

IVA

Tyroidectomy

Ipsilateral IVI

2

52

F

Local (neck lymph node)

2

1a

III

Subtotal thyroidectomy

VI

0

*

68

F


3

1b

IVA

Tyroidectomy

Ipsilateral IVI

1

*

74

F


4a

1b

IVA

Lobectomy

Ipsilateral IVI

2

71

F


4a

1b

IVA

Lobectomy

Ipsilateral IVI

1

83

F


4a

1b

IVA

Tyroidectomy

Ipsilateral IVI

2

56

M


4a

1b

IVA

Tyroidectomy

Ipsilateral IVI

1

69

M


4a

1b

IVA

Tyroidectomy

Bilateral II, III, IV, VI

2

77

F


0

1b

IVA

Tyroidectomy

Ipsilateral II, III, IV, VI

0

76

M


0

1b

IVA

Tyroidectomy

Ipsilateral IVI

0

62

M


3

1b

IVA

Tyroidectomy

Ipsilateral IVI

1

22

F

Distant (lung)

1b

1b

I

Tyroidectomy

Bilateral IVI

0

44

F

Distant (lung, bone)

4a

0

I

Lobectomy

Ipsilateral IVI

2

55

M

Distant (lung, bone)

1b

1b

IVA

Tyroidectomy

Ipsilateral IVI

1

77

M

Distant (lung)

4a

1a

IVA


VI

2

62

F

Distant (lung)

4a

1a

IVA


VI

2

*

*

Note: * successful salvage treatment

Table 1: Characteristics of the patients with local or distant recurrences. pT→

0

1a

1b

2

0

2 {1}

2

1

2

1a

1

9

1

4

12 (1) [2]

2

1

3 (1) {1}

22

4 (1)

3

7 {1}

5 {1}

3 (1) {1} [1]

23

1

1

5

3 {1} [1]

10

9 (1) {2} [1]

9

20

86

1b

3

4

Total

2

9

2 {1}

13

T 2

1 {1}

3 4 Total

4

20

18

11

13

Note: ( ) indicates the number of patients with local recurrence in the thyroid gland. { }indicates the number of the patients with local recurrence in the neck lymph nodes. [ ] indicates the number of the patients with distant recurrence.

Table 2: Pre- and postoperative T stages.

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T

pT

Thyroidectomy

Subtotal Thyroidectomy

Lobectomy

Thyroidectomy

Subtotal Thyroidectomy

Lobectomy

0

5

2

2 {1}

3 {2}

1a

6 {1}

3

4

6

5

9 (1)

1b

10 (2) {1} [2]

3

9

7 (1) [2]

3

8

2

10 (1) {3}

5 {1}

8 (1) [1]

6

2 {1}

3

3

5

3 [1]

2 {1}

8 {2}

4

1

4

3 {1}

3 [1]

3 (1) {1}

9 (2) {3}

5 [2]

6 (1) {2} [1]

39

19

28

Total

1

Note: ( ) indicates the number of patients with local recurrence in the thyroid gland. { } indicates the number of the patients with local recurrence in the neck lymph nodes. [ ] indicates the number of the patients with distant recurrence.

Table 3: T stages and the extent of resection of the thyroid gland. pN

N

0

Total

0

1a

1b

23 (2)

12 {1} [1]

15 (2) {2}

50

3 [1]

1

4

2 [1]

1

29 (1) {7} [2]

32

25

16

45

86

1a 1b Total

Table 4: Pre- and postoperative N stages.

N

pN

Extent of neck dissection 0 none

10 (1)

VI

16 (1) {1} [1]

Ipsilateral II, III, IV, VI

4

Ipsilateral IVI

16 (2) {2}

1a

0

1a

2 [1]

1

7 (1)

11 {1} [2]

3 {1}

2

2

3 {1}

24 (1) {5} [2]

5 [1]

2

34 (3) {7} [1]

1 {1} 4

1b

10 (1)

Bilateral II, III, IV, VI Bilateral IVI

1b

1

mediastinum Total

3 [1]

1 {1} 1

1

1

6 [1] 1

25

16

45

Note: ( ) indicates the number of patients with local recurrence in the thyroid gland. { }indicates the number of the patients with local recurrence in the neck lymph nodes. [ ] indicates the number of the patients with distant recurrence.

Table 5: N stages and the extent of neck dissection.

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Post-operative

Total

I I

26 (1) [2]

II

4 (1)

III

1

II

2

III

IVA

6

5 (1)

37

3 {1}

4 (1)

13

2

3 {1} [1]

6

1

29 (1) {8} [2]

30

12

41

86

Pre-operative

IVA Total

31

2

Note: ( ) indicates the number of patients with local recurrence in the thyroid gland. { }indicates the number of the patients with local recurrence in the neck lymph node. [ ] indicates the number of the patients with distant recurrence.

Table 6: Pre- and postoperative TNM stages.

Independent Variable

Regression Coefficient of Dependent Variable

SE

Age

0.0274

0.0310

Sex

-0.5503

pT

Hazard

95%CI

P Value

1.0278

0.9673-1.0921

0.3760

0.5743

0.5768

0.1871-1.7778

0.3380

0.7005

0.3661

2.0148

0.9831-4.1293

0.0557

pN

-0.3783

0.5238

0.6850

0.2454-1.9123

0.4701

pTNM

2.2306

1.1906

9.3056

0.9022-95.9770

0.0610

Ratio

Table 7: Cox multivariate regression analysis.

Discussion Numerous staging classifications of PTC have been reported. However, there is no consensus regarding the comparison of staging classifications. Brierley et al. [3] applied 10 staging classifications to the cause-specific survival data obtained in a retrospective review of 382 patients with papillary and follicular thyroid carcinoma. They demonstrated that the AJCC/UICC TNM is as good as the AGES, EORTC, MACIS and AMES classification systems and better than the Clinical Class, MSK and Ohio classification systems in predicting outcomes. They concluded that the TNM staging classification should be universally adopted and used for all reports of thyroid carcinoma, as the TNM classification is the most universally available system, and none of the multiple staging systems appear to have any obvious superiority. Lang, et al. [4] applied 14 staging systems identified in a comprehensive MEDLINE search of cases 1965 to 2005 to 589 PTC patients treated between 1961 and 2001. They reported that the three highest staging systems ranked according to the proportion of variation were the MACIS followed by the AJCC/UICC TNM and EORTC. None of the patients in this study had distant metastases at the beginning of treatment. Furthermore, the TNM staging classification has a tendency to affect the survival according to Cox multivariate regression analysis. We concluded that the TNM staging classification is an appropriate staging system for predicting the prognosis.

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The prognosis of PTC is usually excellent: however, a proportion of patients develop recurrence and eventually die from the disease. In this study, five patients developed local recurrences in the thyroid gland, 10 patients developed local recurrences in the neck lymph nodes and five patients developed distant recurrences. Three of the five patients with local recurrences in the thyroid gland were successfully treated with salvage therapy. Nine of 10 patients developed local recurrences in the neck lymph nodes despite undergoing lateral neck dissection. Clinicians must consider countermeasures to prevent local recurrences in the neck lymph nodes. Twenty-seven of the 50 N0 patients were found to have pN1a or pN1b disease. The prognosis of these 27 patients was not necessarily poor compared to that of the N1a and pN1a or N1b and pN1b patients. It has been reported that clinical staging alone is inaccurate, as up to 90% of patients with PTC exhibit micrometastatic involvement of the neck lymph nodes [5,6]. Recently, positron emission tomography/computed tomography (PET/CT) has become available. However, the sensitivity of PET/CT in assessing cervical lymph node disease is poor (30% to 40%) and the diagnostic accuracy of PET/CT and CECT performed on the initial evaluation of the cervical lymph nodes does not differ significantly [7]. The Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer [8] recommend the use of preoperative neck US and US-guided FNA for the routine evaluation of sonographically suspicious lymph nodes, and do not recommend the routine preoperative use of other imaging studies (CT, MRI, PET/CT). Clinicians should actively use neck US to improve the diagnostic accuracy of detecting neck lymph node metastasis.

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doi:http://dx.doi.org/10.4172/2324-8785.1000209 Meanwhile, traditional modalities, including surgical resection followed by radioactive iodine (RAI) ablation and TSH suppression, have been the mainstay of treatment for thyroid carcinoma for most of the 20th century. TSH suppression was performed in all of the patients in this study. Unfortunately, there are no RAI ablation facilities in our hospital. Few randomized studies have addressed the impact of RAI ablation on disease-specific mortality and the relapse rate, while the studies that have addressed this issue are inconclusive. A recent metaanalysis documented the positive effects of RAI ablation as an adjunct to thyroidectomy [9]. On the other hand, the positive effects of RAI ablation may not be apparent when thyroid surgery is performed by highly expert hands at selected tertiary referral centers [10]. The ATA [8] and ESMO [11] guidelines recommended the use of RAI ablation in high-risk patients. It is necessary to consider RAI ablation in patients with advanced-stage disease. There is no role for the routine adjunctive use of chemotherapy in patients with differentiated thyroid cancer. Aberrant signaling pathways have been implicated in the onset, progression and invasiveness of differentiated thyroid carcinoma. The most common genetic changes in patients with PTC are point mutations in BRAF and RAS and rearrangement of the RET proto-oncogene [12,13]. These mutations are known to activate the mitogen-activated protein kinase (MAPK) pathway. Recently, multitargeted kinase inhibitors have emerged as promising treatments for differentiated thyroid carcinoma. Striking and durable disease regression has been induced in many patients treated with drugs such as sorafenib [14,15], sunitinib [16], pazopanib [17] and axitinib [18]. However, all available outcome data have come from single-arm studies. Modulators of angiogenesis appear to play a role in the progression of thyroid and other carcinomas. Vascular endothelial growth factor (VEGF) regulates endothelial cell proliferation and migration. VEGF receptor tyrosine kinases are frequently activated in differentiated thyroid cancer lesions and the surrounding stroma [19]. Leboulleux, et al. [20] reported the efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signaling, in a randomized, double-blind, phase 2 trial. These new multikinase inhibitors targeting the MAPK and angiogenic pathways, are expected to improve the rate of lolcal recurrence in the cervical lymph nodes.

Conclusion This study analyzed the treatment outcomes of papillary thyroid cancer at our hospital. The TNM staging classification is an appropriate staging system for predicting the prognosis. Although most patients have an excellent prognosis, the use of countermeasures against local recurrence in the cervical lymph node is necessary.

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expression in thyroiditis and thyroid carcinoma. J Endocrinol. 161: 41-49. 20. Leboulleux S, Bastholt L, Krause T, de la Fouchardiere C, Tennvall J, et al. (2012) Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol 13: 897-905.

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