Primary tumour size is a prognostic parameter in patients suffering from differentiated thyroid carcinoma with extrathyroidal growth: results of the MSDS trial

in European Journal of Endocrinology

Objective

The Multicentre Study Differentiated Thyroid Cancer (MSDS) collective represents a well-defined group of patients with thyroid carcinomas with extrathyroidal extension. The aim of the present study was to evaluate the relationship of the primary tumour size with clinicopathological features as well as the outcome of patients with minimum and extensive extrathyroidal growth (pT3b- and pT4a-tumours; UICC 2002/2003, 6th ed).

Methods

The tumour diameter was available in 324 out of 351 MSDS patients (244 females, 80 males). Mean age of patients was 47.7±12.0 years (range, 20.1–69.8 years), and the median follow-up was 6.2 years. The relationship between primary tumour size and the following clinicopathological data was investigated: age, gender, histological tumour type (papillary thyroid carcinomas (PTC) versus follicular thyroid carcinomas (FTC)) and UICC/AJCC TNM classification. In addition, the correlation between primary tumour size and event-free and overall survival was assessed.

Results

The FTC of our series were significantly larger than PTC (3.46 vs 1.84 cm; P<0.001). Patients suffering from pT3b-tumours presented with significantly smaller tumour size than those with extensive extrathyroidal growth (pT4a-tumours) (1.9 vs 3.0 cm; P<0.01). All patients with distant metastases suffered from tumours >2 cm. Furthermore, event-free and overall survival were significantly correlated with increasing tumour size (P<0.05). Using multivariate analysis, a pT4a-category and a tumour diameter >2 cm remained independent predictors of survival.

Conclusions

In patients suffering from differentiated thyroid carcinoma with extrathyroidal growth (pT3b and pT4a), the tumour size is an independent predictor of event-free and overall survival.

Abstract

Objective

The Multicentre Study Differentiated Thyroid Cancer (MSDS) collective represents a well-defined group of patients with thyroid carcinomas with extrathyroidal extension. The aim of the present study was to evaluate the relationship of the primary tumour size with clinicopathological features as well as the outcome of patients with minimum and extensive extrathyroidal growth (pT3b- and pT4a-tumours; UICC 2002/2003, 6th ed).

Methods

The tumour diameter was available in 324 out of 351 MSDS patients (244 females, 80 males). Mean age of patients was 47.7±12.0 years (range, 20.1–69.8 years), and the median follow-up was 6.2 years. The relationship between primary tumour size and the following clinicopathological data was investigated: age, gender, histological tumour type (papillary thyroid carcinomas (PTC) versus follicular thyroid carcinomas (FTC)) and UICC/AJCC TNM classification. In addition, the correlation between primary tumour size and event-free and overall survival was assessed.

Results

The FTC of our series were significantly larger than PTC (3.46 vs 1.84 cm; P<0.001). Patients suffering from pT3b-tumours presented with significantly smaller tumour size than those with extensive extrathyroidal growth (pT4a-tumours) (1.9 vs 3.0 cm; P<0.01). All patients with distant metastases suffered from tumours >2 cm. Furthermore, event-free and overall survival were significantly correlated with increasing tumour size (P<0.05). Using multivariate analysis, a pT4a-category and a tumour diameter >2 cm remained independent predictors of survival.

Conclusions

In patients suffering from differentiated thyroid carcinoma with extrathyroidal growth (pT3b and pT4a), the tumour size is an independent predictor of event-free and overall survival.

Introduction

The diameter of the primary tumour has been described as a determinant for outcome in differentiated thyroid cancer. It has been suggested that a larger tumour size is related to other phenomena associated with worse prognosis, such as extrathyroidal growth, multifocality, locoregional and distant metastases (1). Accordingly, primary tumour size has been included in a variety of scoring schemes (AGES, AMES and MACIS) (2, 3, 4). However, the delineation between low-risk and high-risk tumour size is unsettled. Mazzaferri & Kloos (5) defined a tumour diameter >4 cm as a significant predictive factor for a high-risk situation. Machens et al. (1) found a sharply increased risk of distant metastases for primary tumours larger than about 2 cm, whereas Verburg et al. (6) reported a threshold tumour size of about 1 cm. The prognostic value of these upper limits in diameters was evaluated mainly for intrathyroidal carcinomas. It remains unclear, whether or not the diameter of the tumour is also prognostically relevant for tumours with perithyroidal infiltration (pT3b and pT4a, former 6th edition of the UICC TNM classification 2002/2003) (7, 8). In the recent 7th edition, the differentiation between pT3a (intrathyoidal tumour >4 cm) and pT3b (tumour with minimal perithyroidal infiltration) was cancelled (9). But clinically it remains of ongoing interest to have separate data on carcinomas with minimal perithyroidal infiltration. It was the aim to assess the relationship between the primary tumour size and different clinicopathological data using the well-defined prospective Multicentre Study Differentiated Thyroid Cancer (MSDS) collective with thyroid carcinomas with extrathyroidal growth. The large database allows for retrospective scientific analysis of a multitude of parameters collected over a follow-up time of up to 9 years. In particular, the correlation between primary tumour size and clinical outcome was assessed.

Materials and methods

Patients

Study design

The MSDS trial is a prospective, randomised study which was conducted in Germany, Austria and Switzerland. It has been registered at http://clinicaltrials.gov (ID NCT00144079) in order to determine the benefit of adjuvant radiotherapy in patients with differentiated thyroid carcinoma showing extrathyroidal growth (pT4; UICC 1997) with or without lymph node metastases and without known distant metastases (M0). Inclusion criteria were age between 18 (incl.) and 70 years (excl.) at the time of initial surgery, completion of primary surgical therapy with R0- or R1-resection, Karnofsky index ≥70% and freedom from distant metastases at the time of initial radioiodine therapy (10, 11, 12). Exclusion criteria were poorly differentiated (insular) thyroid carcinoma, secondary cancer and R2-resection with macroscopic tumour residues. Cases were seen by a reference pathologist (K W S) and reclassified if necessary.

Patients who agreed to randomisation were randomised into treatment arms A (external beam radiotherapy) or B (no external beam radiotherapy) at the time of the first 131I-scintigraphy 3–4 months after initial radioiodine therapy. The MSDS treatment protocol included total thyroidectomy with central lymphadenectomy, radioiodine therapy to ablate the thyroid remnant and TSH-suppressive therapy with l-thyroxine (TSH <0.1 mU/l) (13, 14). Radioiodine therapy was to be given under endogenous TSH stimulation after 4 weeks' withdrawal of l-thyroxine using standard activities of 3–4 GBq with a post-therapeutic whole body scintigraphy. If scintigraphic 131I uptake by the thyroid remnant was visible 3–4 months after radioiodine therapy under TSH stimulation, a second fraction of radioiodine therapy was to be given. At the time of each whole body scan, TSH, serum thyroglobulin (Tg), Tg recovery, anti-Tg antibodies and blood cell count were required as well as an ultrasound examination of the neck.

For patients in the treatment arm A, radiotherapy was begun after complete elimination of documented cervical 131I uptake in a diagnostic whole body scan (11). Radiotherapy included the thyroid bed with a dose of 59.4 and 66.6 Gy after R0- and R1-resection respectively and the regional lymph nodes of the neck and upper mediastinum including the posterior cervical chain from the mandible and mastoid process to the tracheal bifurcation with a dose of 50.4 and 54.0 Gy in pN0 and pN1/x diseases respectively. 131I whole body scan, cervical ultrasound and serum Tg under endogenous or exogenous recombinant TSH stimulation were performed 3 months and 1 year after the last ablative radioiodine therapy and thereafter at 2-year intervals. Out-patient follow-up visits were scheduled at half-year intervals (12). Owing to a recruitment deficit for radiotherapy, the randomisation arm was closed in 2003, and the trial was continued as a prospective multicentre study.

All patients diagnosed with differentiated thyroid cancer before January 2003 were staged according to the 5th edition AJCC/UICC TNM staging criteria (15). For the purpose of the present study, these patients were retrospectively restaged or reclassified in accordance to the staging criteria outlined in the 6th edition AJCC/UICC TNM classification (7), used until the end of 2009: 307 (94.8%) patients were assigned to stage pT3b, 17 (5.2%) to stage pT4a (UICC 2002/2003), 137 (42.3%) to AJCC stage I (pT3b-patients <45 years), 173 (53.4%) to stage III, and 14 (4.3%) to stage IVA, but there were no patients with pT4b-tumours. Median follow-up time was 6.2 years. The relationship between primary tumour size and the following clinicopathological data was investigated: age, gender, histological tumour type and UICC/AJCC TNM classification. In addition, the correlation between primary tumour size and event-free and overall survival was assessed. Finally, the patients were subdivided arbitrarily into three groups according to their tumour size group I (≤1.0 cm, n=85), group II (>1.0 to ≤2.0 cm, n=136) and group III (>2.0 cm, n=103).

Ethical approval was obtained from the joint ethical board of the University of Münster and the locoregional physician's chamber of Westfalen-Lippe. In addition, the votes were collected from the local ethical boards. Informed consent was obtained from patients in accordance with the Declaration of Helsinki.

Statistical analysis

The relationship between primary tumour size on the one hand and classified age (<45/≥45 years), gender, histology and the UICC/AJCC TNM classification on the other hand was analysed and tested for statistical significance using the Mann–Whitney–Wilcoxon and the Kruskal–Wallis tests. The correlation between classified tumour size and appearance of recurrence was tested for statistical significance using χ2-test. Kaplan–Meier analysis and the log-rank test were used to analyse event-free and overall survival curves and to estimate event-free rates. An event was defined as an occurrence of a local recurrence, lymph node recurrence, distant metastasis or death after the achievement of a total, clinical tumour-free status. Complete remission was defined as no evidence of disease, i.e. negative tumour parameters: serum Tg measurement, radioiodine WBS and sonographic/radiological examinations. Partial remission was defined as a reduction in tumour parameters without reaching complete remission under therapy. Stable disease was defined as no change in tumour parameters. Progressive disease was defined as an increase in tumour parameters without therapy response.

Multivariate analysis of reviewed prognostic factors was performed using Cox regression. The variables were dichotomised as follows: age: <45 vs ≥45 years; gender: female versus male, histology: follicular thyroid carcinoma (FTC) versus papillary thyroid carcinoma (PTC); tumour diameter: ≤2 vs >2 cm and UICC/AJCC TNM classification (6th ed): pT3b versus pT4a and pN1 versus pN0/X. Statistical analyses were performed using PASW Statistics 18 for Windows (SPSS Inc., Chicago, IL, USA). A P value <0.05 was regarded as significant.

Results

From 2000 to 2004, 351 patients were included in the MSDS trial. Completion of primary surgical therapy was achieved by one operation in 35% of patients, by two operations in 59% and by three operations in 7% of patients. Systematic lymphadenectomy was performed in 72% of patients. Patients received a mean cumulative radioiodine activity of 6.5±5.0 GBq. Additional radiotherapy was performed in 26 patients. The follow-up data of 347 out of 351 MSDS patients were available. The exact tumour diameter was documented in 324 (92.3%; 244 females and 80 males) patients. The mean age of the 324 patients was 47.7±12.0 years (range, 20.1–69.8 years). Histological tumour typing revealed 302 (93.2%) PTC and 22 (6.8%) FTC.

FTC showed a significantly larger tumour size than PTC (3.46 vs 1.84 cm; P<0.001). In addition, there was a significant difference between the tumour size in pT3b- and pT4a-categories. Patients suffering from tumours with minimum extrathyroidal extension (pT3b; UICC 2002/2003) presented with a significantly smaller tumour diameter than those with extensive extrathyroidal growth (pT4a; UICC 2002) (1.9 vs 3.0 cm; P<0.01; Table 1). There were no significant differences in primary tumour size with respect to age and gender. pT4a-tumours showed a minimum tumour diameter of at least 1.2 cm (Fig. 1). Patients with initial lymph node metastases had significantly larger primary tumours than those without lymphogenic spread (2.2 vs 1.8 cm; P<0.001). During a median follow-up of 6.2 years, 303 (93.5%) patients reached complete remission, and 5 (1.5%) reached partial remission. Three (0.9%) patients had stable disease, and 13 (4.0%) patients suffered from progressive disease.

Table 1

Distribution of tumour size of the MSDS patients. The variables were dichotomised as follows: age: <45 vs ≥45 years; gender: female versus male; histology: follicular thyroid carcinoma (FTC) versus papillary thyroid carcinoma (PTC); T-category: pT3b versus pT4a (6th ed); N-category: pN1 versus pN0/X (6th ed); UICC/AJCC stages: I versus III versus IVA.

nMean (cm)s.d. (cm)Median (cm)Minimum (cm)Maximum (cm)SignificanceP<0.05=significant
<45 years1371.991.241.800.107.00<45 vs ≥45 yearsNSa
≥45 years1871.921.531.500.2010.00
Male802.181.571.800.3010.00Male versus femaleNSa
Female2441.881.361.500.109.50
PTC3021.841.261.500.109.50PTC versus FTCP<0.001a
FTC223.462.342.901.0010.00
pT3b3071.901.371.500.1010.00pT3b versus pT4aP<0.01a
pT4a172.961.852.401.208.50
N0/X1941.821.511.400.2010.00N0/X versus N1P<0.001a
N11302.151.231.900.106.80
I1371.991.241.800.107.00Global: P<0.01b
I versus III:P<0.05a
III1731.851.491.400.2010.00I versus IVA:P<0.05a
IVA142.841.832.201.208.50III versus IVA:P<0.01a

Tested with Mann–Whitney–Wilcoxon test.

Tested with Kruskal–Wallis test.

Figure 1

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Figure 1

Box–Whisker plot showing the tumour sizes of MSDS patients with pT3b- and pT4a-tumours (6th ed) respectively according to the AJCC/UICC classification 2002/2003. Circles and asterisks denote mild and extreme outliers respectively.

Citation: European Journal of Endocrinology 163, 4; 10.1530/EJE-10-0116

In 22 (6.8%) patients, recurrences were noted after previously documented complete remission (Table 2). Median delay between primary treatment and diagnosis of recurrence was 1.3 years. Seventeen (77.3%) recurrences occurred in patients with PTC and five (22.7%) occurred in patients with FTC. Eighteen (5.6%) patients had locoregional tumour recurrences. Seven (2.2%) patients showed recurrences in more than one location. Eleven (3.4%) patients presented during follow-up with distant metastases. All of the latter suffered from tumours >2 cm (group III) (Table 3).

Table 2

Characteristics of patients with recurrent disease or fatal outcome after previously documented complete remission.

CaseAge (years)GenderpT-cat.TD (cm)Histology, variantRecurrenceRTxOutcome
123f3b0.10PTC, conventional typeLNCR
241f3b0.90PTC, conventional typeLNPD
324f3b1.00PTC, conventional typeLNCR
448f3b1.10PTC, tall cellLNCR
541m3b1.30PTC, conventional typeLNCR
649f4a1.80PTC, conventional typeLNCR
758m4a1.80PTC, follicularParatrachealCR
831f3b2.00PTC, conventional typeLNCR
951f3b2.30PTC, conventional typeLungPD
1066f4a2.40PTC, follicularLNCR
1162f3b2.50PTC, conventional typeLNDeath
1229f3b2.50FTCLungDeath
1329f3b2.60PTC, conventional typeLN, lungPD
1459m3b2.70FTC, oncocyticParatracheal, lung+PD
1561m3b3.00PTC, conventional typeLN, lungPD
1647f3b3.00PTC, follicularDeath (accident)
1748m3b3.00FTC LN, lungPD
1867m4a3.10PTC, conventional typeLN, lungPR
1951m4a3.50FTC LungCR
2067m4a4.00PTC, conventional typeParatrachealPD
2143f3b4.00PTC, oncocyticParatracheal, LN, lungPD
2237f3b4.00FTC Mediastinal, lungPD
2366m3b6.80PTC, conventional typeParatracheal, LN, brainDeath

f, female; m, male; pT-cat., pT-category (6th ed); TD, primary tumour diameter; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; LN, lymph node; RTx, percutaneous radiotherapy; outcome, status of disease at the end of follow-up; CR, complete remission; PR, partial remission and PD, progressive disease.

Table 3

Classified tumour size and appearance of recurrence.

Locoregional recurrencesDistant metastases
Tumour size++
≤1.0 cm823850
>1.0 to ≤2.0 cm13151360
>2.0 cm93109211
Total3061831311
NSaP<0.001a

P value <0.05 was regarded as significant.

Tested with χ2-test.

Event-free survival was significantly correlated with tumour size (Fig. 2). Patients with tumours ≤2 cm (groups I and II) suffered significantly less events than those with tumours >2 cm (group III) (P<0.01). In addition, there was a statistically significant difference in the event-free survival between pT3b-patients in groups I and II and those within group III (P<0.01). Accordingly, a significant threshold tumour diameter of 2 cm was also found with respect to the event-free survival of patients with AJCC stage III (P<0.001). Using multivariate analysis, a tumour diameter >2 cm and a pT4a-category remained independent predictors of event-free survival (Table 4).

Figure 2

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Figure 2

Event-free survival of the MSDS patients according to tumour size in pT3b- and pT4a-carcinomas (6th ed). Group I (≤1.0 cm), group II (>1.0 to ≤2.0 cm) and group III (>2.0 cm) (I versus II: P=NS; I versus III: P<0.05; II versus III: P<0.01, total: P<0.01).

Citation: European Journal of Endocrinology 163, 4; 10.1530/EJE-10-0116

Table 4

Multivariate analysis of prognostic factors for event-free survival. Hazard ratio gives the probability of the prognostic factor for an event in comparison to the opposed specification (age: <45 vs ≥45 years; gender: female versus male; histology: follicular thyroid carcinoma (FTC) versus papillary thyroid carcinoma (PTC); tumour size: ≤2 vs >2 cm; T-category: pT3b versus pT4a (6th ed); N-category: pN1 versus pN0/X (6th ed)). 95% confidence interval (CI) represents the 95% CI.

Prognostic factorHazard ratio95% CIP
Age (≥45 years)0.980(0.396; 2.425)0.966
Gender (female)0.820(0.325; 2.070)0.674
Histology (FTC)2.930(0.949; 9.046)0.062
Tumour diameter (>2 cm)2.833(1.172; 6.850)0.021
T-category (pT4a)3.230(1.097; 9.513)0.033
N-category (N1)2.565(0.985; 6.676)0.054

P values were calculated by the Cox regression (Wald test). P value <0.05 was regarded as significant.

Owing to the small number of pT4a-patients, predictive factors of recurrences were also studied in the large subgroup of pT3b-patients. Tumour size remained a significant predictor of tumour recurrence using multivariate analysis. In addition, histology was a prognostic factor for event-free survival (P<0.01; Table 5).

Table 5

Multivariate analysis of prognostic factors for event-free survival within subgroup pT3b. Hazard ratio gives the probability of the prognostic factor for an event in comparison to the opposed specification (age: <45 vs ≥45 years; gender: female versus male; histology: follicular thyroid carcinoma (FTC) versus papillary thyroid carcinoma (PTC); tumour size: ≤2 vs >2 cm; N-category: pN1 versus pN0/X (6th ed)). 95% confidence interval (CI) represents the 95% CI.

Prognostic factorHazard ratio95% CIP
Age (≥45 years)0.723(0.271; 1.933)0.518
Gender (female)0.874(0.304; 2.517)0.803
Histology (FTC)5.500(1.532; 19.743)0.009
Tumour diameter (>2 cm)2.902(1.035; 8.139)0.043
N-category (N1)2.559(0.878; 7.463)0.085

P values were calculated by the Cox regression (Wald test). P value <0.05 was regarded as significant.

Overall survival of the MSDS patients was excellent. Only three (0.9%) patients showed fatal tumour progress; additionally one patient died from a road accident. Overall survival was significantly correlated with tumour size (P<0.05; Fig. 3). This correlation was still significant if the patient involved in the fatal accident was excluded from the analysis. Percutaneous radiotherapy had no significant impact on the correlation between primary tumour size and event-free or overall survival. Only one irradiated patient showed a local recurrence and pulmonary metastases (Table 2).

Figure 3

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Figure 3

Overall survival of the MSDS patients according to tumour size in pT3b- and pT4a-carcinomas (6th ed). Group I (≤1.0 cm), group II (>1.0 to ≤2.0 cm) and group III (>2.0 cm). (I versus II: P=NS; I versus III: P=NS; II versus III: P<0.05, total: P<0.05).

Citation: European Journal of Endocrinology 163, 4; 10.1530/EJE-10-0116

Discussion

The MSDS trial represents the largest multi-institutional cohort of high-risk patients with differentiated thyroid cancer patients worldwide second to the North American National Thyroid Cancer Treatment Cooperative Study (12, 16, 17). Inclusion criteria were PTC and FTC with extrathyroidal extension and without known distant metastases at the time of primary diagnosis. All the patients were treated by thyroidectomy, radioiodine therapy and TSH-suppression. Because of its highly standardised monitoring system, this database is well suited for retrospective scientific population studies.

It is widely accepted that the size of the primary tumour is of prognostic value in patients with differentiated thyroid cancer (18). In addition, this parameter diameter is correlated with well-known risk factors such as extrathyroidal growth, multifocality and metastasis (1). Whereas the tumour size has been directly integrated in the UICC/AJCC classification for intrathyroidal tumours, this is not the case for extrathyroidal tumours (7). Therefore, it was the aim to assess the impact of the primary tumour size in the large cohort of patients suffering from differentiated thyroid carcinoma with extrathyroidal growth included in the MSDS trial. However, it remains unclear, whether or not the diameter of the tumour is also prognostically relevant for tumours with perithyroidal infiltration (pT3b and pT4a, UICC 2002/2003). There was a uniform distribution of the primary tumour sizes with respect to age (<45 vs ≥45 years) and gender. However, the FTC of this study were significantly larger than PTC. According to the literature, FTC are 6–18 mm larger than their papillary counterparts (19, 20, 21) which is in accordance with our data presented. The mean tumour size of the MSDS patients with FTC was 3.5 cm, whereas PTC showed a mean tumour diameter of 1.8 cm. This may be due to a delay in tumour diagnosis because fine needle aspiration cytology does not enable a distinction between follicular carcinoma and follicular adenoma (22). According to the ‘linear tumour progression model’, FTC develop from follicular adenoma in a sequential progressive manner. The genetic defect ultimately leading to malignancy has to occur in a certain time period before vascular and/or capsular invasion, as the histological hallmarks for the diagnosis of FTC, are fully developed (23). This concept may explain the exceptionally rare occurrence of small FTC in our study. In addition, the higher prevalence of lymph node metastases may lead to an earlier clinical manifestation of PTC compared with follicular carcinomas (1). Whereas the mean tumour dimensions in the pT4a-category were significantly larger than those in the pT3b-category, the maximum tumour size was higher in the latter. This may be due to a delayed clinical manifestation of primarily intrathyroidal lesions compared with those with extrathyroidal extension to clinically more apparent structures such as subcutaneous soft tissues, larynx, trachea, oesophagus or recurrent laryngeal nerve (7). It may, however, also be due to a less aggressive tumour biology. To the best of our knowledge, this is the first report on the minimum diameter of 1.2 cm of pT4a-tumours. Interestingly, this figure is above that of thyroid microcarcinomas measuring 1.0 cm or less in diameter (24, 25). Thus, according to our study, thyroid carcinomas measuring ≤1 cm seem to show a very small risk of extensive infiltrative growth requiring classification within the pT4a-category (UICC 2002/2003). In case of guideline compatible therapeutic management and follow-up, these patients have survival rates indistinguishable from those of the normal population (26). Interestingly, the whole group of high-risk MSDS patients showed an excellent overall and event-free survival. This may be due to the following reasons. First, the excellent overall and event-free survival in this series of high-risk patients may be due to the standardised diagnostic and therapeutic management in the MSDS trial. Secondly, the MSDS patients benefit from their lifelong medical surveillance in the framework of a clinical study (27). Thereby, other health hazards and potential fatal diseases can be revealed at an earlier stage, making cure possible. Thirdly, strict inclusion and exclusion criteria were applied in the MSDS trial. In particular, the patients with poorly differentiated (insular) thyroid carcinoma, secondary cancer and R2-resection were excluded.

The initial pN status was also correlated with tumour size. On average, the patients with lymph node metastasis had significantly larger primary tumours than those without documented lymphogenic spread. This finding is in accordance with definitions of a threshold tumour diameter for an increased risk of lymphogenic metastasis. Two studies reported anchoring points of a tumour size-adjusted cumulative risk for nodular metastases at about 0.5–2.0 cm (1, 6).

In the present study, both the overall survival and the event-free survival were significantly correlated with increasing tumour size (Figs 2 and 3). Patients with tumours >2 cm (group III) showed significantly higher event rates than those with tumours ≤2 cm (groups I and II). About 5.6% of the patients had locoregional tumour recurrences, and 3.4% presented with distant metastases. All the patients in the latter group suffered from carcinomas >2 cm (group III). It is well known that distant metastasis is the single most important determinant for an unfavourable prognosis. Therefore, the early identification of patients prone to the development of distant metastasis is a major challenge. The primary tumour size within the pT3b- and pT4a-groups may be a relevant predictor of distant metastasis. A tumour diameter >4 cm has been generally accepted as a significant predictor of a high-risk situation (5). This threshold should be applied with caution in view of the poorer prognosis of tumours >2 cm if extrathyroidal extension is present. In particular, the lack of division of pT3-tumours into those with and without extrathyroidal extension in the current UICC/AJCC TNM classification should be reconsidered in view of the present findings (8, 9).

Conclusion

In patients suffering from differentiated thyroid carcinoma with extrathyroidal growth and without initial distant metastasis, primary tumour size is related to the histological tumour type, degree of extrathyroidal extension and lymph node metastasis. In addition, the tumour diameter is an independent predictor of event-free and overall survival in these patients.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

The MSDS trial is funded by the German Cancer Aid (Projects No. 70-2294 and 10-8723) and supported by the Federal Ministry of Education and Research, Germany (MoBiMed subproject 01EZ0809).

Acknowledgements

MSDS study group

Study chairman: Prof. Dr O Schober.* Vice chairman: Prof. Dr H Dralle (Halle-Wittenberg).* Study coordinators: Prof. Dr M Biermann,* Prof. Dr B Riemann.*

Reference centres: Biometrics: Dr A Heinecke,* Prof. Dr W Köpcke.* Pathology: Prof. Dr K W Schmid* (Essen). Surgery: Prof. Dr H Dralle (Halle)*. Radiotherapy: Prof. Dr A Schuck,* Prof. Dr N Willich.* Clinical monitoring: Prof. Dr Chr. Reiners,* Dr M Geling (Würzburg). Independent Data Monitoring and Safety Committee: Prof. Dr H W Hense (Münster; chairman), Prof. Dr H Jürgens,* Prof. Dr L Kiesel, PD Dr P-A Löschmann (Münster). Members of the MSDS steering committee are indicated by an asterisk (*).

MSDS study participants (nuclear medicine; number of patients contributed to the current analysis in parentheses): B Riemann, Michaela K Pixberg, M Weckesser, O Schober, Münster (55); M Dietlein, C Kobe, H Schicha, Köln (44); H Schlemmer, H Lerch, Wuppertal (31); U Dörr †, Gabriele Pöpperl, Stuttgart (30); M Richter, Jana Grimm, Traute Mende, Halle (23); G Farmakis, Ursula Nestle, D Hellwig, C Alexander, C Kirsch, Homburg/Saar (19); Birgit Schryen, S Ladner, C Reiners, Würzburg (18); Jessika Schmitt-Makula, T Zajic, E Moser, Freiburg (15); N Achajew, A Szikszai, C Eilles, Regensburg (14); Waltraud Eichhorn, M Schreckenberger, Mainz (13); Christina Greb, Nicole Bena-Boupda, Dagmar Steiner, R Bauer, Gießen (10); H Amthauer, Peggy Fostitsch, R Steinke, Magdeburg (8); Sandra Rosenbaum, R Görges, A Bockisch, Essen (8); S Ahuja, F Gottschalk, Frankfurt/O (8); Cornelia Puskás, J Peter, F Maul, Karlsruhe (8); G Meisetschläger, K Scheidhauer, M Schwaiger, München (8); J Müller, Eva Weckesser, W Knapp, Hannover (8); A Becherer, R Dudczak, Wien (7); J Borkopp, Gerlinde Thiemann, B Theophil, Dortmund (7); Birte Diekmeyer, Elisabeth Ostwald-Lenz, H Wieler, Koblenz (7); A Schneider, B Hackmann, B Piotrowski, Hamm (6); Gerhild Kumnig, P Lind, Klagenfurt (6); P Groth, C Schümichen, Rostock (5); A Szikszai, A Schwarz, E Fiedler, T Kuwert, Erlangen (4); Gabriele Holl, R Schöneich, Potsdam (4); H Steinert, G von Schulthess, Zürich (4); C Glosemeyer, Katrin Weigel, J Kropp, Ch. Dschietzig, Cottbus (4); P Panholzer, Sigrid Pöcher, Elfriede Rechberger, W Langsteger, Linz (4); Vika Müller, M Clausen, Hamburg (3); M Hofmann, A Glasow, J Werhand, P Lindner, Hildesheim (3); M J Reinhardt, R Niemann, Angelika Deutschmann, G Klaushenke, Oldenburg (3); Nicole Mittemeyer, G Frese, J Feldkamp, J Herrmann, Bielefeld (3); J Diener, F Grünwald, G Hör, Frankfurt (2); S Wedekind, R Nastvogel, H Philipp, M Schmidt, Bamberg (2); K Kley, H Müller, Düsseldorf (1); M Schmücking, R Baum, Bad Berka (1); H Huber, Wilhelmine Maschek, Linz (1); M Fischer, E Bell, Dernbach (1); M Tosch, R Aurisch, Mönchengladbach (1); Isabel Lauer, M Bähre, E Richter, Lübeck (1); H I Lux, H Tonscheid, K Hering, Dortmund (1); M Hacker, P Knesewitsch, K Hahn, München (1); R Thiele, Schwäbisch Hall (1); J Hoffend, Sabine Haufe, U Haberkorn, Heidelberg (1); K Biermann, S Ezziddin, K von Mallek, H Biersack, Bonn (1). *MSDS study group.

References

  • 1

    MachensAHolzhausenHJDralleH. The prognostic value of primary tumor size in papillary and follicular thyroid carcinoma. A comparative analysis. Cancer200510322692273doi:10.1002/cncr.21055.

  • 2

    HayIDGrantCSTaylorWFMcConaheyWM. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery198710210881095.

  • 3

    HayIDBergstralhEJGoellnerJREbersoldJRGrantCS. 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. Surgery199311410501057.

  • 4

    VoutilainenPESiironenPFranssilaKOSivulaAHaapiainenRKHaglundCH. AMES, MACIS and TNM prognostic classifications in papillary thyroid carcinoma. Anticancer Research20032342834288.

  • 5

    MazzaferriELKloosRT. Clinical review 128: current approaches to primary therapy for papillary and follicular thyroid cancer. Journal of Clinical Endocrinology and Metabolism20018614471463doi:10.1210/jc.86.4.1447.

  • 6

    VerburgAMäderULusterMReinersC. Primary tumor diameter as a risk factor for advanced disease features of differentiated thyroid carcinoma. Clinical Endocrinology200971291297doi:10.1111/j.1365-2265.2008.03482.x.

  • 7

    Sobin LH & Wittekind Ch. Thyroid gland – rules for classification. In UICC TNM Classification of Malignant Tumors 6th edn pp 52–56. Eds LH Sobin & Ch Wittekind. New York: Wiley-Liss 2002.

  • 8

    Wittekind C Greene FL Henson DE Hutter RVP & Sobin LH. A commentary on uniform use. In TNM Supplement 3rd edn p 138. Eds Wittekind C Greene FL Henson DE Hutter RVP & Sobin LH. New York: Wiley-Liss 2003.

  • 9

    Sobin LH Gospodarowicz MK & Wittekind Ch. Thyroid gland – rules for classification. In UICC TNM Classification of Malignant Tumors 7th edn pp 58–62. Eds LH Sobin MK Gospodarowicz MK & Ch Wittekind. New York: Wiley-Liss 2009.

  • 10

    BiermannMPixbergMKSchuckAHeineckeAKöpckeWSchmidKWDralleHWillichNSchoberO. Multicenter study differentiated thyroid carcinoma (MSDS). Diminished acceptance of adjuvant external beam radiotherapy. Nuklearmedizin200342244250.

  • 11

    SchuckABiermannMPixbergMKMüllerSBHeineckeASchoberOWillichN. Acute toxicity of adjuvant radiotherapy in locally advanced differentiated thyroid cancer. First results of the multicenter study differentiated thyroid cancer. Strahlentherapie und Onkologie2003179832839doi:10.1007/s00066-003-1158-1.

  • 12

    BiermannMPixbergMRiemannBSchuckAHeineckeASchmidKWWillichNDralleHSchoberOMSDS study group. Clinical outcomes of adjuvant external-beam radiotherapy for differentiated thyroid cancer. Nuklearmedizin2009488998.

  • 13

    PaciniFSchlumbergerMDralleHEliseiRSmitJWWiersingaWEuropean Thyroid Cancer Taskforce. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. European Journal of Endocrinology2006154787803doi:10.1530/eje.1.02158.

  • 14

    LusterMClarkeSEDietleinMLassmannMLindPOyenWJTennvallJBombardieriEEuropean Association of Nuclear Medicine (EANM). Guidelines for radioiodine therapy of differentiated thyroid cancer. European Journal of Nuclear Medicine and Molecular Imaging20083519411959doi:10.1007/s00259-008-0883-1.

  • 15

    Sobin LH & Wittekind Ch. Thyroid gland – rules for classification. In UICC TNM Classification of Malignant Tumors 5th edn pp 47–50. Eds LH Sobin & Ch Wittekind. New York: Wiley-Liss 1997.

  • 16

    LerchHSchoberOKuwertTSaurHB. Survival of differentiated thyroid carcinoma studied in 500 patients. Journal of Clinical Oncology19971520672075.

  • 17

    ShermanSIBrierleyJDSperlingMAinKBBigosSTCooperDSHaugenBRHoMKleinILadensonPWRobbinsJRossDSSpeckerBTaylorTMaxonHRIII. Prospective multicenter study of thyroid carcinoma treatment: initial analysis of staging and outcome. National Thyroid Cancer Treatment Cooperative Study Registry Group. Cancer19988310121021doi:10.1002/(SICI)1097-0142(19980901)83:5<1012::AID-CNCR28>3.0.CO;2-9.

  • 18

    VerburgFAMäderULusterMReinersC. Histology does not influence prognosis in differentiated thyroid carcinoma when accounting for age, tumour diameter, invasive growth and metastases. European Journal of Endocrinology2009160619624doi:10.1530/EJE-08-0805.

  • 19

    MazzaferriELJhiangSM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. American Journal of Medicine199497418428doi:10.1016/0002-9343(94)90321-2.

  • 20

    HundahlSACadyBCunninghamMPMazzaferriEMcKeeRFRosaiJShahJPFremgenAMStewartAKHölzerS. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer200089202217doi:10.1002/1097-0142(20000701)89:1<202::AID-CNCR27>3.0.CO;2-A.

  • 21

    ChowSMLawSCAuSKLeungTWChanPTMendenhallWMLauWH. Differentiated thyroid carcinoma: comparison between papillary and follicular carcinoma in a single institute. Head and Neck200224670677doi:10.1002/hed.10080.

  • 22

    CeruttiJMDelceloRAmadeiMJNakabashiCMacielRMPetersonBShoemakerJRigginsGJ. A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expression. Journal of Clinical Investigation200411312341242doi:10.1172/JCI19617.

  • 23

    SchmidKWFaridNR. How to define follicular thyroid carcinoma?Virchows Archiv2006448385393doi:10.1007/s00428-006-0162-0.

  • 24

    DeLellisRALloydRVHeitzPUEngC. Tumours of the thyroid and parathyroid. In World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs pp. 49134. Eds DeLellisRALloydRVHeitzPUEngCLyon: IARC Press2004.

  • 25

    SassolasGHafdi-NejjariZRemontetLBossardNBelotABerger-DutrieuxNDecaussin-PetrucciMBournaudCPeixJLOrgiazziJBorson-ChazotF. Thyroid cancer: is the incidence rise abating?European Journal of Endocrinology20091607179doi:10.1530/EJE-08-0624.

  • 26

    AroraNTurbendianHKKatoMAMooTAZarnegarRFaheyTJIII. Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two?Thyroid200919473477doi:10.1089/thy.2008.0185.

  • 27

    PeppercornJMWeeksJCCookEFJoffeS. Comparison of outcomes in cancer patients treated within and outside clincal trials: conceptual framework and structured review. Lancet2004363263270doi:10.1016/S0140-6736(03)15383-4.

(Please see Acknowledgements)

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Figures

  • View in gallery

    Box–Whisker plot showing the tumour sizes of MSDS patients with pT3b- and pT4a-tumours (6th ed) respectively according to the AJCC/UICC classification 2002/2003. Circles and asterisks denote mild and extreme outliers respectively.

  • View in gallery

    Event-free survival of the MSDS patients according to tumour size in pT3b- and pT4a-carcinomas (6th ed). Group I (≤1.0 cm), group II (>1.0 to ≤2.0 cm) and group III (>2.0 cm) (I versus II: P=NS; I versus III: P<0.05; II versus III: P<0.01, total: P<0.01).

  • View in gallery

    Overall survival of the MSDS patients according to tumour size in pT3b- and pT4a-carcinomas (6th ed). Group I (≤1.0 cm), group II (>1.0 to ≤2.0 cm) and group III (>2.0 cm). (I versus II: P=NS; I versus III: P=NS; II versus III: P<0.05, total: P<0.05).

References

1

MachensAHolzhausenHJDralleH. The prognostic value of primary tumor size in papillary and follicular thyroid carcinoma. A comparative analysis. Cancer200510322692273doi:10.1002/cncr.21055.

2

HayIDGrantCSTaylorWFMcConaheyWM. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery198710210881095.

3

HayIDBergstralhEJGoellnerJREbersoldJRGrantCS. 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. Surgery199311410501057.

4

VoutilainenPESiironenPFranssilaKOSivulaAHaapiainenRKHaglundCH. AMES, MACIS and TNM prognostic classifications in papillary thyroid carcinoma. Anticancer Research20032342834288.

5

MazzaferriELKloosRT. Clinical review 128: current approaches to primary therapy for papillary and follicular thyroid cancer. Journal of Clinical Endocrinology and Metabolism20018614471463doi:10.1210/jc.86.4.1447.

6

VerburgAMäderULusterMReinersC. Primary tumor diameter as a risk factor for advanced disease features of differentiated thyroid carcinoma. Clinical Endocrinology200971291297doi:10.1111/j.1365-2265.2008.03482.x.

7

Sobin LH & Wittekind Ch. Thyroid gland – rules for classification. In UICC TNM Classification of Malignant Tumors 6th edn pp 52–56. Eds LH Sobin & Ch Wittekind. New York: Wiley-Liss 2002.

8

Wittekind C Greene FL Henson DE Hutter RVP & Sobin LH. A commentary on uniform use. In TNM Supplement 3rd edn p 138. Eds Wittekind C Greene FL Henson DE Hutter RVP & Sobin LH. New York: Wiley-Liss 2003.

9

Sobin LH Gospodarowicz MK & Wittekind Ch. Thyroid gland – rules for classification. In UICC TNM Classification of Malignant Tumors 7th edn pp 58–62. Eds LH Sobin MK Gospodarowicz MK & Ch Wittekind. New York: Wiley-Liss 2009.

10

BiermannMPixbergMKSchuckAHeineckeAKöpckeWSchmidKWDralleHWillichNSchoberO. Multicenter study differentiated thyroid carcinoma (MSDS). Diminished acceptance of adjuvant external beam radiotherapy. Nuklearmedizin200342244250.

11

SchuckABiermannMPixbergMKMüllerSBHeineckeASchoberOWillichN. Acute toxicity of adjuvant radiotherapy in locally advanced differentiated thyroid cancer. First results of the multicenter study differentiated thyroid cancer. Strahlentherapie und Onkologie2003179832839doi:10.1007/s00066-003-1158-1.

12

BiermannMPixbergMRiemannBSchuckAHeineckeASchmidKWWillichNDralleHSchoberOMSDS study group. Clinical outcomes of adjuvant external-beam radiotherapy for differentiated thyroid cancer. Nuklearmedizin2009488998.

13

PaciniFSchlumbergerMDralleHEliseiRSmitJWWiersingaWEuropean Thyroid Cancer Taskforce. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. European Journal of Endocrinology2006154787803doi:10.1530/eje.1.02158.

14

LusterMClarkeSEDietleinMLassmannMLindPOyenWJTennvallJBombardieriEEuropean Association of Nuclear Medicine (EANM). Guidelines for radioiodine therapy of differentiated thyroid cancer. European Journal of Nuclear Medicine and Molecular Imaging20083519411959doi:10.1007/s00259-008-0883-1.

15

Sobin LH & Wittekind Ch. Thyroid gland – rules for classification. In UICC TNM Classification of Malignant Tumors 5th edn pp 47–50. Eds LH Sobin & Ch Wittekind. New York: Wiley-Liss 1997.

16

LerchHSchoberOKuwertTSaurHB. Survival of differentiated thyroid carcinoma studied in 500 patients. Journal of Clinical Oncology19971520672075.

17

ShermanSIBrierleyJDSperlingMAinKBBigosSTCooperDSHaugenBRHoMKleinILadensonPWRobbinsJRossDSSpeckerBTaylorTMaxonHRIII. Prospective multicenter study of thyroid carcinoma treatment: initial analysis of staging and outcome. National Thyroid Cancer Treatment Cooperative Study Registry Group. Cancer19988310121021doi:10.1002/(SICI)1097-0142(19980901)83:5<1012::AID-CNCR28>3.0.CO;2-9.

18

VerburgFAMäderULusterMReinersC. Histology does not influence prognosis in differentiated thyroid carcinoma when accounting for age, tumour diameter, invasive growth and metastases. European Journal of Endocrinology2009160619624doi:10.1530/EJE-08-0805.

19

MazzaferriELJhiangSM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. American Journal of Medicine199497418428doi:10.1016/0002-9343(94)90321-2.

20

HundahlSACadyBCunninghamMPMazzaferriEMcKeeRFRosaiJShahJPFremgenAMStewartAKHölzerS. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer200089202217doi:10.1002/1097-0142(20000701)89:1<202::AID-CNCR27>3.0.CO;2-A.

21

ChowSMLawSCAuSKLeungTWChanPTMendenhallWMLauWH. Differentiated thyroid carcinoma: comparison between papillary and follicular carcinoma in a single institute. Head and Neck200224670677doi:10.1002/hed.10080.

22

CeruttiJMDelceloRAmadeiMJNakabashiCMacielRMPetersonBShoemakerJRigginsGJ. A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expression. Journal of Clinical Investigation200411312341242doi:10.1172/JCI19617.

23

SchmidKWFaridNR. How to define follicular thyroid carcinoma?Virchows Archiv2006448385393doi:10.1007/s00428-006-0162-0.

24

DeLellisRALloydRVHeitzPUEngC. Tumours of the thyroid and parathyroid. In World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs pp. 49134. Eds DeLellisRALloydRVHeitzPUEngCLyon: IARC Press2004.

25

SassolasGHafdi-NejjariZRemontetLBossardNBelotABerger-DutrieuxNDecaussin-PetrucciMBournaudCPeixJLOrgiazziJBorson-ChazotF. Thyroid cancer: is the incidence rise abating?European Journal of Endocrinology20091607179doi:10.1530/EJE-08-0624.

26

AroraNTurbendianHKKatoMAMooTAZarnegarRFaheyTJIII. Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two?Thyroid200919473477doi:10.1089/thy.2008.0185.

27

PeppercornJMWeeksJCCookEFJoffeS. Comparison of outcomes in cancer patients treated within and outside clincal trials: conceptual framework and structured review. Lancet2004363263270doi:10.1016/S0140-6736(03)15383-4.

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