help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-1443
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wada, N.
Right arrow Articles by Imada, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wada, N.
Right arrow Articles by Imada, T.
Related Collections
Right arrow Thyroid
Right arrow Endocrine Oncology
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 215-218
Copyright © 2007 by The Endocrine Society

BRIEF REPORT

Prognostic Value of the Sixth Edition AJCC/UICC TNM Classification for Differentiated Thyroid Carcinoma with Extrathyroid Extension

Nobuyuki Wada, Hirotaka Nakayama, Nobuyasu Suganuma, Yoshihiko Masudo, Yasushi Rino, Munetaka Masuda and Toshio Imada

Department of General Surgery, Yokohama City University Hospital and Medical Center, 3-9 Fukuura, Kanazawa-ku, Yokohama City, Kanagawa 236-0004, Japan

Address all correspondence and requests for reprints to: Nobuyuki Wada, M.D., Department of General Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama City, Kanagawa 236-0004, Japan. E-mail: Wadan523{at}aol.com.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: The prognostic value of the sixth edition AJCC/UICC TNM classification is currently unclear.

Objective: The aim was to evaluate the prognostic value of the sixth edition.

Design and Patients: We retrospectively assessed 354 primary differentiated thyroid carcinomas (77 men and 277 women; age, 51.2 yr; follow-up, 107.6 months) between 1964 and 2003. Sixty percent of patients underwent lobectomy, 40% underwent subtotal/total thyroidectomy, and only 2% were given radioiodine. There were 153, 104, 86, and 11 patients in fifth stages I, II, III, and IV, and 175, 76, 14, 68, 10, and 11 patients in sixth stages I, II, III, IVA, IVB, and IVC, respectively.

Results: New T1–3 had no significant influence. In Cox proportional hazard analysis, T4a and T4b were significantly related to disease-specific survival (DSS). We separately analyzed 68 patients (age 45 yr or older) with extrathyroid extension. These T4 (fifth) tumors were reclassified as 6 T3, 52 T4a, and 10 T4b tumors. The 10-yr DSS rates were 100, 69.3, and 10.0% for T3, T4a, and T4b, respectively. T4b exhibited worse prognoses compared with T4a (P < 0.0001; hazard ratio, 10.1; 95% confidence interval, 4.1–25.3). Stages I and II in both editions achieved favorable prognoses. The 10-yr DSS rates were 67.0 and 27.3% in fifth stages III and IV, and 100, 74.5, 10.0, and 27.3% in sixth stages III, IVA, IVB, and IVC, respectively. DSS curves differed significantly between all sixth TNM stages (P < 0.0001).

Conclusion: The sixth edition more accurately predicts different outcomes according to the revised criteria for the degree of extrathyroid extension.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
VARIOUS RISK DEFINITIONS for thyroid carcinoma have been evaluated (1, 2, 3, 4, 5, 6, 7, 8, 9). The American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) tumor-node-metastasis (TNM) classification has been used in clinical practice for differentiated thyroid carcinoma (DTC). This classification has also been evaluated to determine its utility in discriminating patients who have distinct outcomes (5, 6, 7, 8, 9). The fifth edition AJCC/UICC TNM classification (1997) was revised as the sixth edition in 2002 (10). A major alteration was the reclassification of tumor staging (T). Fifth edition T1 (≤1 cm) and T2 (between 1 and 4 cm) were redefined as sixth edition T1 (≤2 cm) and T2 (between 2 and 4 cm). However, there are controversial reports that the new definition of T1 or T2 had only a minor impact on survival or was impractical for papillary thyroid carcinoma (11, 12). In the sixth edition, T3 includes not only large tumors (4 cm or more) but also tumors with minimal extension, and T4 consists of T4a and T4b. Thus, the sixth edition divides fifth edition T4 tumors into T3 (minimal invasion), T4a (extended invasion), and T4b (more extensive unresectable invasion) tumors according to the degree of extrathyroid extension. The degree of extension has been closely related to adverse prognoses (6, 13, 14, 15, 16, 17, 18). Therefore, the sixth edition is expected to predict more accurately different outcomes in patients with extrathyroid extension compared with the fifth edition.

The aim of the present study was to evaluate the prognostic value of the sixth edition AJCC/UICC TNM classification for DTCs, especially in those with extrathyroid extension.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

A total of 498 primary DTCs were treated surgically at our institution between 1964 and 2003. For the present analysis, adequate medical information was not available in 144 (28.9%) patients because the information for the extent of invasion, nodal status, or outcomes was incomplete. Therefore, 354 (71.1%) patients (77 men and 277 women; mean age, 51.2 yr; mean follow-up, 107.6 months) were assessed retrospectively. This study was approved by the Human Research Committee of Yokohama City University.

There were 322 (91.0%) papillary and 32 (9.0%) follicular carcinomas, which were confirmed pathologically. Specific variants such as Tall cell or insular carcinoma were excluded. The mean tumor size was 2.7 ± 1.5 cm. There were 153, 104, 86, and 11 patients in fifth edition stages I, II, III, and IV, and 175, 76, 14, 68, 10, and 11 patients in sixth edition stages I, II, III, IVA, IVB, and IVC, respectively. Thyroid resection was lobectomy for 211 (59.6%) patients and subtotal/total thyroidectomy for 143 (40.4%) patients. Subtotal/total thyroidectomy was performed in 46 (30.1%), 42 (40.4%), 47 (54.7%), and 8 (72.7%) patients in fifth stages I, II, III, and IV, and in 52 (29.7%), 33 (43.4%), 7 (50.0%), 40 (58.8%), 3 (30.0%), and 8 (72.7%) patients in sixth stages I, II, III, IVA, IVB, and IVC, respectively. Six patients with minimal extension in sixth stage III underwent subtotal or total thyroidectomy. Thirty-nine of 52 patients with T4a tumor in stage IVA exhibited laryngotracheal invasion (eight laryngectomies and 31 tracheal resections). Node dissection was performed in 129 (84.3%), 96 (92.3%), 77 (89.5%), and 8 (72.7%) patients in fifth stages I, II, III, and IV, and in 148 (84.6%), 71 (93.4%), 11 (78.6%), 64 (94.1%), 5 (50.0%), and 11 (100%) patients in sixth stages I, II, III, IVA, IVB, and IVC, respectively. A total of 271 (76.6%) patients underwent TSH suppression. Radioactive iodine (RI) therapy was only performed in selected patients due to the fact that in Japan the use of RI is strictly controlled, and the number of centers performing RI therapy is extremely limited. RI therapy was performed in two stage IVA and five stage IVC patients. Extra beam radiotherapy (EBRT) was performed in three stage IVA and four stage IVB patients.

Tumor stage conversion in patients with extrathyroid extension

We also separately evaluated outcomes in 68 patients (age 45 yr or older) who had tumor with extrathyroid extension and no distant metastasis at diagnosis. In the fifth edition, these tumors were classified equivalently as T4. These 68 were divided into six T3, 52 T4a, and 10 T4b tumors according to the revised criteria for extrathyroid extension. Additionally, in the new definition 55 tumors changed from T2 (fifth) to T1 (sixth).

Evaluation of clinical outcomes

Disease-free survival (DFS) and disease-specific survival (DSS) were evaluated. Recurrence was defined as local disease arising from remnant thyroid tissue or regional nodes, or as distant disease metastasizing to other organs and was found in clinical and radiological examinations, thyroglobulin monitoring, ultrasound, x-ray, and/or computed tomography.

Statistical analysis

DFS and DSS were assessed with Kaplan-Meier analysis and compared using the log-rank test. The effects of T category, N category, and TNM stage on DSS were evaluated by univariate analysis using the Cox proportional hazards models [hazard ratio (HR), 95% confidence interval (CI)]. Differences were considered significant when P values were less than 0.05. Statistical analyses were performed with StatView version 5.0 (SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Overall, recurrence and disease death occurred in 77 (21.8%) and 34 (9.6%) patients. Local recurrence, distant metastasis, and both occurred in 43, 16, and 18 patients.

Table 1Go summarizes the outcomes by T category, N category, and TNM stage.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Clinical outcomes by different T category, N category, and TNM stage in the fifth and sixth TNM classifications

 
DSS rates for T1–3 in both editions ranged from 94.1 to 100%. In the fifth edition, T4 (P < 0.0001, HR 11.5, 95% CI 4.8–28.0) affected DSS. In the sixth edition, T4a (P = 0.0007, HR 5.4, 95% CI 2.0–14.3) and T4b (P < 0.0001, HR 54.2, 95% CI 19.7–149.2) affected DSS. As shown in Fig. 1Go, statistical significance was not calculated for the fifth and sixth edition T1 tumors because there was no disease death (Fig. 1Go, A and B). However, the DSS curves (Fig. 1BGo) apparently differed between T1–3, T4a, and T4b tumors.


Figure 1
View larger version (16K):
[in this window]
[in a new window]

  		FIG. 1. The DSS curves by T category and TNM stage in the fifth and sixth editions. Statistical significance was not calculated for the fifth and sixth edition T1 tumors because there were no patients who died of disease (A and B). However, the DSS curves (B) by T category were apparently different between T1–3, T4a, and T4b tumors. The DSS curves (C) differed significantly between all four fifth TNM stages (P < 0.0001). Furthermore, those (D) differed significantly between all six sixth TNM stages (P < 0.0001).

 
Table 1Go also presents the outcomes according to the sixth edition in 68 patients (age 45 yr or older) with extrathyroid extension. The 10-yr DFS and DSS rates were 66.7 and 100% for T3, 39.8 and 69.3% for T4a, and 10.0 and 10.0% for T4b, respectively. T4b was related more significantly to DSS than T4a (P < 0.0001, HR 10.1, 95% CI 4.1–25.3).

In the fifth edition, N1a (P = 0.0034, HR 3.9, 95% CI 1.6–9.7) and N1b (P < 0.0001, HR 11.0, 95% CI 5.0–24.3) affected DSS. In the sixth edition, N1b (P < 0.0001, HR 7.2, 95% CI 3.5–14.8) affected DSS.

As summarized in Table 1Go, stages I and II in both editions achieved favorable DSS. In the fifth edition, stages III and IV were significantly related to reduced DSS. The 10-yr DFS and DSS rates were 41.9 and 67.0% in stage III and 0 and 27.3% in stage IV, respectively. In the sixth edition, stages IVA, IVB, and IVC were significantly related to reduced DSS. The 10-yr DFS and DSS rates were 66.7 and 100% in stage III, 44.4 and 74.5% in stage IVA, 10.0 and 10.0% in stage IVB, and 0 and 27.3% in stage IVC, respectively. As shown in Fig. 1Go, DSS curves (Fig. 1CGo) differed significantly between all four fifth TNM stages (P < 0.0001). Furthermore, those (Fig. 1DGo) differed significantly between all six sixth TNM stages (P < 0.0001).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
There are two major differences between the fifth and sixth editions of the AJCC/UICC TNM classification. The first is the revised definition for T1 tumors. The sixth edition T1 tumors comprise all tumors up to 2 cm. In our series, 55 tumors had a change from T2 (fifth) to T1 (sixth). However, such tumor stage conversion did not influence DSS.

Another major alteration is the new classification for extrathyroid extension. Various risk definitions include tumor extension as an adverse indicator (1, 2, 3, 4, 5, 6, 7, 8, 9). However, the degree of extension was not thoroughly assessed because only the presence or absence of extension was described in many risk definitions. In the fifth edition, extrathyroid extensions were classified equivalently as T4 regardless of the various degrees of extension. In the sixth edition, these were divided into T3, T4a, and T4b according to the degree of extension. This new classification for extrathyroid extension is considered most important, and we therefore evaluated whether this alteration is valuable to predict different outcomes. Our overall results revealed that T4b tumors (HR 54.2) had worse DSS than T4a tumors (HR 5.4). In addition, our series included seven younger patients (<45 yr of age) with T4a tumor, and they achieved favorable prognosis. Older age is generally associated with an adverse prognosis (5, 17, 18).

We separately evaluated 68 patients (age 45 yr or older) who had tumors with extrathyroid extension and no distant metastasis at diagnosis. These were the same T4 tumors (fifth). The outcomes in these 68 patients differed significantly between the new tumor stages, T3, T4a, and T4b. None of the six patients with minimal extension (T3) died of disease. Minimal extension had a minor impact on outcomes (11, 14), similar to our current investigation, while T4b (P < 0.0001, HR 10.1) had a worse DSS than T4a. Thus, the new definition for tumor extension is considered valuable to predict different outcomes according to the various degree of extension.

Regarding N category, this study found that the fifth edition N1a and N1b affected DSS, whereas the sixth edition N1a did not. These results may suggest that the new definition of N category has no advantage.

In the present analyses for TNM stage grouping, stages I and II in both editions exhibited favorable prognoses. The 10-yr DFS and DSS rates were 41.9 and 67.0% in fifth stage III, whereas they were 66.7 and 100% in sixth stage III. These results suggest that sixth stage III is considered a low to moderate risk group. Similarly, those rates were 44.4 and 74.5% in stage IVA, 10 and 10% in stage IVB, and 0 and 27.3% in stage IVC, respectively. Outcomes in fifth stage IV and sixth stage IVC were the same. Thus, stage IVA is an intermediate risk group, and stages IVB and IVC are critical risk groups.

TSH suppression, EBRT, and RI therapy are successful adjuvant therapies (7, 15, 16, 19, 20). EBRT is valuable for controlling local disease. RI therapy is effective for eradicating malignant tumor cells at local and distant sites. Only selected patients in our series received radiotherapies. We consider that increased use of radiotherapies may influence our results. Adjuvant radiotherapies could be important in our future practice.

Finally, lobectomy and node dissection were performed in about 65 and 90% of our patients in stages I and II, respectively. They achieved favorable prognoses. We therefore consider that such treatment differences may be allowed as regional practice for some lower stage patients when the use of RI is limited.

Conclusion

Sixth edition stages I and II achieved favorable prognoses. Stage III represents the low to moderate risk group. Stage IVA is an intermediate risk group. Stages IVB and IVC are critical high-risk groups. The sixth edition TNM classification more accurately predicts outcomes in patients with extrathyroid extension according to the revised criteria for the degree of extension, but we found no advantage in the new definitions of T1 and T2 or N category.


   Footnotes
 
Disclosure Summary: The authors have nothing to disclose.

First Published Online October 31, 2006

Abbreviations: CI, Confidence interval; DFS, disease-free survival; DSS, disease-specific survival; DTC, differentiated thyroid carcinoma; EBRT, extra beam radiotherapy; HR, hazard ratio; RI, radioactive iodine.

Received July 5, 2006.

Accepted October 23, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Cady B, Rossi R 1988 An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 104:947–953[Medline]
  2. Hay ID, Grant CS, Taylor WF, McConahey WM 1987 Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 102:1088–1095[Medline]
  3. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS 1993 Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 114:1050–1057[Medline]
  4. DeGroot LJ, Kaplan EL, McCormick M, Straus FH 1990 Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 71:414–424[Abstract/Free Full Text]
  5. Lo CY, Chan WF, Lam KY, Wan KY 2005 Follicular thyroid carcinoma: the role of histology and staging systems in predicting survival. Ann Surg 242:708–715[CrossRef][Medline]
  6. Palme CE, Waseem Z, Raza SN, Eski S, Walfish P, Freeman JL 2004 Management and outcome of recurrent well-differentiated thyroid carcinoma. Arch Otolaryngol Head Neck Surg 130:819–824[Abstract/Free Full Text]
  7. Loh KC, Greenspan FS, Gee L, Miller TR, Yeo PP 1997 Pathological tumor-node-metastasis (pTNM) staging for papillary and follicular thyroid carcinomas: a retrospective analysis of 700 patients. J Clin Endocrinol Metab 82:3553–3562[Abstract/Free Full Text]
  8. Brierley JD, Panzarella T, Tsang RW, Gospodarowicz MK, O’Sullivan B 1997 A comparison of different staging systems predictability of patient outcome. Thyroid carcinoma as an example. Cancer 79:2414–2423[CrossRef][Medline]
  9. Lundgren CI, Hall P, Dickman PW, Zedenius J 2006 Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case-control study. Cancer 106:524–531[CrossRef][Medline]
  10. Sobin LH, Wittekind CH 2002 UICC: TNM classification of malignant tumors. 6th ed. New York: Wiley-Liss
  11. Dobert N, Menzel C, Oeschger S, Grunwald F 2004 Differentiated thyroid carcinoma: the new UICC. 6th ed. TNM classification system in a retrospective analysis of 169 patients. Thyroid 14:65–70[CrossRef][Medline]
  12. Passler C, Scheuba C, Asari R, Kaczirek K, Kaserer K, Niederle B 2005 Importance of tumour size in papillary and follicular thyroid cancer. Br J Surg 92:184–189[CrossRef][Medline]
  13. Ortiz S, Rodriguez JM, Soria T, Perez-Flores D, Pinero A, Moreno J, Parrilla P 2001 Extrathyroid spread in papillary carcinoma of the thyroid: clinicopathological and prognostic study. Otolaryngol Head Neck Surg 124:261–265[CrossRef][Medline]
  14. Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, Kuma K, Miyauchi A 2006 Prognostic significance of extrathyroid extension of papillary thyroid carcinoma: massive but not minimal extension affects the relapse-free survival. World J Surg 30:780–786[CrossRef][Medline]
  15. McCarty TM, Kuhn JA, Williams Jr WL, Ellenhorn JD, O’Brien JC, Preskitt JT, Lieberman ZH, Stephens J, Odom-Maryon T, Clarke KG, Wagman LD 1997 Surgical management of thyroid cancer invading the airway. Ann Surg Oncol 4:403–408[Abstract]
  16. Farahati J, Reiners C, Stuschke M, Muller SP, Stuben G, Sauerwein W, Sack H 1996 Differentiated thyroid cancer. Impact of adjuvant external radiotherapy in patients with perithyroidal tumor infiltration (stage pT4). Cancer 77:172–180[CrossRef][Medline]
  17. Shaha AR, Shah JP, Loree TR 1996 Risk group stratification and prognostic factors in papillary carcinoma of thyroid. Ann Surg Oncol 3:534–538[Abstract]
  18. Andersen PE, Kinsella J, Loree TR, Shaha AR, Shah JP 1995 Differentiated carcinoma of the thyroid with extrathyroidal extension. Am J Surg 170:467–470[CrossRef][Medline]
  19. Kebebew E, Clark OH 2003 Locally advanced differentiated thyroid cancer. Surg Oncol 12:91–99[CrossRef][Medline]
  20. Brierley J, Tsang R, Panzarella T, Bana N 2005 Prognostic factors and the effect of treatment with radioactive iodine and external beam radiation on patients with differentiated thyroid cancer seen at a single institution over 40 years. Clin Endocrinol (Oxf) 63:418–427[CrossRef][Medline]



This article has been cited by other articles:


Home page
 JCOHome page
A. A. Onitilo, J. M. Engel, C. I. Lundgren, P. Hall, L. Thalib, and S. A.R. Doi
Simplifying the TNM System for Clinical Use in Differentiated Thyroid Cancer
J. Clin. Oncol., April 10, 2009; 27(11): 1872 - 1878.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Surg. Oncol.Home page
N. Wada, K. Masudo, H. Nakayama, N. Suganuma, K. Matsuzu, S. Hirakawa, Y. Rino, M. Masuda, and T. Imada
Recommendation for Subclass Evaluation of TNM stage IVA Papillary Thyroid Carcinomas: T4aN1b Patients Are at Risk for Recurrence and Survival
Ann. Surg. Oncol., May 1, 2008; 15(5): 1511 - 1517.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wada, N.
Right arrow Articles by Imada, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wada, N.
Right arrow Articles by Imada, T.
Related Collections
Right arrow Thyroid
Right arrow Endocrine Oncology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals