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J. Endocrinol. Invest. 31: 1032-1037, 2008

ABSTRACT. Background: Papillary thyroid carcinomas are as-sociated with metastases and decreased survival in a smallgroup of patients. Aim: The aim of this study is to determinethe factors associated with recurrences/metastases in papil-lary thyroid carcinoma patients. Subjects and methods: Onehundred and thirty-one patients with papillary thyroid carci-noma were evaluated retrospectively. The diagnosis was pap-illary microcarcinoma (PMC) in 48 patients. All patients hadundergone near-total/total thyroidectomy. Radioactive io-dine was given to 103 patients. Age at diagnosis, gender,previous history of thyroid disease, tumor stage, histopatho-logical characteristics of tumor and initial treatment strate-gies were evaluated. Results: Recurrences/metastases de-veloped in 17 patients during follow-up. Recurrences devel-oped at a significantly higher percentage in patients with atumor stage >T1 and patients with lymph node metastasisat presentation. No significant difference was observed in

recurrence ratio between patients with PMC and patientswith a tumor diameter ≥≥1cm. In the Cox-regression analysisonly the advanced tumor stage (>T1) and presence of lymphnode metastases were found to be significant predictors forrecurrence (univariate analysis, odds ratio =4.02 and 3.15,respectively). However, multivariate analysis did not revealany significant independent predictors. According to the Ka-plan-Meier survival analysis, lymph node metastases at pre-sentation were associated with a decrease in recurrence-freesurvival at statistical significance (p=0.05). No mortality wasobserved during follow-up. Conclusion: Papillary thyroid car-cinoma leads to recurrences/metastases in a small group ofpatients. Initial characteristics of the patients – i.e. presenceof lymph node metastases – may predict recurrences/metas -tases in these patients. (J. Endocrinol. Invest. 31: 1032-1037, 2008)©2008, Editrice Kurtis

INTRODUCTION

Papillary thyroid carcinomas have a good prognosis butmay lead to metastases and decreased survival in a smallgroup of patients. Several prognostic factors for recur-rences/metastases, including age, certain histologic sub-types, tumor size, local tumor invasion or lymph nodemetastases were suggested (1, 2). However, there aresome uncertainties about the factors leading to recur-rences/metastases. Previous studies indicated that lymphnode involvement at presentation might have a protec-tive effect and might suggest a better survival (3-6), al-though several studies indicated the opposite (1, 2, 7-13). Papillary microcarcinomas represent a group of papillarycancer assumed to have an excellent prognosis. Howev-er, they may also lead to recurrences/metastases andeven mortality. Pellegriti et al. (13) indicated that 25.7%of patients with papillary thyroid cancer <1.5 cm devel-oped relapsed/persistent disease after primary treatment.In this study we evaluated the prognostic factors for re-currences in a group of patients with papillary thyroidcancer-including microcancers.

MATERIALS AND METHODS

Patients between 1985 and 2004 with a follow-up period of at least6 months were evaluated retrospectively. The study group con-

sisted of 131 patients (83 patients with papillary thyroid cancer (≥1cm) and 48 patients with papillary microcancer (<1 cm). Patientswith undifferentiated or poorly differentiated papillary thyroid can-cer and patients with thyroid cancer with a follow-up period <6months were excluded. Patients were evaluated according to age,sex, primary therapeutic approach, histopathological findings atinitial examination, recurrence/metastases during follow-up. Initialtumor stage was evaluated according to the Tumor Node Metas-tases (TNM) (1992) classification. Patients with papillary thyroidcancer >1 cm were regarded as papillary cancer (PC) patients andpatients with a tumor size <1 cm were regarded as papillary mi-crocancer (PMC) patients. PMC was found incidentally in 33 pa-tients who underwent operation for multinodular goiter.Primary surgical procedure was total or near-total thyroidectomyfor all patients. One hundred and three patients underwent ra-dioactive iodine (131I) ablation after surgery. It was decided tofollow up 28 patients without 131I ablation treatment. Fixed dos-es of 131I were used: 50 or 100 mCi doses were selected for rem-nant ablation. For patients with lymph node metastases, 150mCi dose of 131I was used. For patients with distant metastases,175-200 mCi doses were preferred. Routine follow-up proce-dure after thyroidectomy (and 131I) was as follows: a whole bodyscan (WBS) was performed for patients who received therapeu-tic doses of 131I. Uptake outside the neck indicated distantmetastasis at presentation (1 patient had pulmonary uptake af-ter initial dose of 131I). Thereafter levothyroxine (L-T4) treatmentwas initiated to suppress TSH concentrations <0.1 mIU/l. TSHand thyroglobulin (Tg) measurements were performed at 3months under L-T4 suppression therapy. Patients were also eval-uated at the 6th month. Neck ultrasonography was performedat the 6th month and thereafter yearly. A diagnostic 131I scan 9-12 months after 131I therapy was performed for patients treat-ed with 131I initially. For the first diagnostic WBS after 131I ther-apy, thyroid hormone was withdrawn. TSH and Tg levels wereobtained and 5 mCi 131I was given. Remission was defined as

*This study has been presented in part at the European Congress of Endocrinology,2005, Goteborg-Sweden as a poster (Abstract No: P3-15).

Key-words: Metastasis, papillary microcancer, prognosis, survival, thyroid cancer.

Correspondence: N. Ozbey, MD, Tozkoparan Mah, Kopuz Sok, Cevahir Koru Sitesi,D Blok, D:10, Merter, 34010, Istanbul, Turkey.

E-mail: nozbey@hotmail.com

Accepted March 28, 2008.

Prognostic factors in patients with papillary thyroid carcinoma*O. Soyluk1, F. Selcukbiricik1, Y. Erbil2, A. Bozbora2, Y. Kapran3, and N. Ozbey4

1Department of Medicine; 2Department of Surgery; 3Department of Pathology; 4Division of Endocrinology, Department ofMedicine, Medical Faculty, Istanbul University, Istanbul, Turkey

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no uptake on WBS and undetectable serum Tg concentrations(<1 ng/ml) in association with negative anti-Tg antibodies, whenpatients were hypothyroid (TSH>30 mIU/l). Patients treated andfollowed-up between years 1985 and 1995 were re-evaluatedbetween years 2000 and 2004 by 131I WBS and endogen or re-combinant TSH stimulated Tg concentrations to ensure remis-sion according to these criteria.For patients who were not given 131I treatment, remission wasdefined as undetectable Tg concentrations and negative anti-Tg antibodies on L-T4 treatment in association with a normalneck ultrasonography, indicating no residual tissue or patho-logical lymph nodes. Patients in remission were followed-up atyearly intervals, with a clinical examination, a serum Tg mea-surement on L-T4 treatment, and neck ultrasonography. Recur-rence was defined as the evidence of disease after at least 6months’ disease-free follow-up. Recurrent disease was deter-mined according to the physical examination, detectable (>1ng/ml) Tg concentrations on L-T4 treatment, neck ultrasonogra-phy, 131I imaging results, X-rays, computed tomogra-phy/magnetic resonance imaging or histopathological exami-nation when necessary. Local bed recurrences were diagnosedaccording to the ultrasonographic findings ,131I WBS results in-dicating uptake in thyroid bed, and fine needle aspiration biop-sy or local tissue excision results.Serum Tg, anti-Tg, and TSH concentrations were measured byElecsys method (Roche/Hitachi Modular System-Japan). Statistical analyses were performed by NCSS 2000 software. De-scriptive statistical methods were used in addition to analysis ofvariance. Tukey multiple comparison test, Student t-test, Chi-square test and Fischer’s exact test were used where appropri-ate. Kaplan-Meier analysis was applied to determine recurrence-free survival and log-rank test was used to evaluate the differ-ences between curves. Age, gender, tumor stage (T1-4), multi-focality, tumor invasion, and lymph node metastases were tak-

en into account to predict the recurrences/metastases. Univari-ate and multivariate analysis of prognostic variables were per-formed according to the Cox proportional hazard model. A p-value <0.05 was considered significant.

RESULTS

Demographic parameters of the study group were shown inTable 1. Patients with PMC were significantly older com-pared with patients with PC. No statistically significant dif-ference was observed between male/female ratio. Previoushistory of thyroid disease was observed in 82 patients. In75 patients the previous diagnosis was goiter. Hyperthy-roidism was observed in 7 patients. No significant differ-ence was observed with respect to the frequency of hyper-thyroidism and goiter between patients with PC and PMC.All patients underwent near total/total thyroidectomy.One hundred and three out of 131 patients received 131I(Table 1). Twenty-eight patients were treated by near to-tal/total thyroidectomy only (Table 1). Ten patients withPC and 18 patients with PMC underwent near total/totalthyroidectomy only. In patients with PMC, only surgerywas more frequently applied. The patients were classi-fied according to the T of the TNM classification. Thenumber of patients with a tumor stage of T1 was signifi-cantly higher in the PMC group as expected. Patientswith PC had significantly higher T4 tumors compared withPMC patients. Lymph node metastases at presentationwere also significantly increased in PC group. Only onepatient with PC had pulmonary metastases at initial eval-uation. The patient with pulmonary metastases at initialpresentation was treated by operation and 131I. The pa-tient was in remission after initial treatment and no re-currences developed during follow-up. Mean follow-up

Papillary cancer Papillary microcancer p(no.=83) (no.=48)

Female/male (no.) 68/15 38/10 ns

Age (mean) (yr) 38.7±12.8 45.1±8.9 <0.01(range) 13-67 30-70

Goiter (no.) 42 33 ns

Hyperthyroidism (no.) 3 4 ns(Graves disease) (1) (1)(Toxic adenom) (1) (2)(Toxic multinodular goiter) (1) (1)

Surgery (no.) 10 18

Surgery+RAI 73 30 <0.01

TNM-TT1 3 32 <0.001T2 33 - <0.001T3 1 - nsT4 46 16 <0.05

TNM-NN0 57 45N1 26 3 <0.001

TNM-MM0 82 48M1 1 - ns

Follow-up (yr) 7.67±5.23 5.06±3.42 <0.05

Range (yr) (1-22) (1-19)

TNM: tumor node metastases classification; RAI: radioiodine.

Table 1 - Study characteristics of the patients.

O. Soyluk, F. Selcukbiricik, Y. Erbil, et al.

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period was significantly longer in patients with PC com-pared with PMC patients.No statistically significant difference was found betweenincidental and non incidental PMC patients regardingstudy parameters and follow-up findings (Table 2).First 131I doses and total 131I doses during follow-up werenot significantly different between PC and PMC patients(111±33 vs 106±15 mCi for initial doses and 156±112 vs109±29 mCi for total doses respectively, p>0.05).Recurrent/metastatic disease was identified in 17 out of131 patients (12.9%) during follow-up (local bed recurrencein 5 patients, cervical lymph node metastases in 3 patients,and distant metastases in 6 patients for PC group; localbed recurrence in 2 patients and cervical lymph nodemetastases in 1 patients for PMC group, p>0.05). Recurrences were regarded as a whole group becauseof the small sample size. Patient with recurrences (no.=17)and without recurrences (no.=114) were compared withrespect to initial characteristics (Table 3). Twenty-eight

patients in the “without recurrence” group and 5 patientsin the “recurrence” group had T2 tumors. Only 1 patientin the “recurrence” group has T3 tumor. For statisticalpurposes, T2, T3, and T4 tumors were evaluated as awhole group. Advanced tumor stage (>T1), presence ofinitial lymph node metastases and relatively low dose ini-tial 131I treatment were found to be significantly higherin patients with recurrence.The prognostic value of the variables for recurrence wasstudied in univariate and multivariate analysis using Coxproportional hazard model (Table 4). Initial tumor stage>T1 and presence of lymph node metastases were sig-nificant predictors of recurrence according to the uni-variate analysis. However, multivariate analysis did notreveal any significant predictors.According to Kaplan-Meier survival analysis, gender, age,primary treatment modality (surgery vs surgery±131I), Tstage of the tumor, presence of thyroid capsule invasionhad no significant effect on disease-free survival.

�ncidental PMC patients Non-incidental PMC p(operated for multinodular goiter) patients

(no.=33) (no.=15)

Female/male (no.) 27/6 11/4 ns

Age 46.8±10.2 43.7±7.3 ns

Initial treatment (no.)Surgery 10 8Surgery+RAI 23 7 ns

TNM-N (no.)N0 30 15N1 3 - ns

Multifocality (no.) 9 1 ns

Vascular invasion (no.) 4 - ns

Soft tissue invasion (no.) 4 2 ns

Initial RAI dose (mCi) 108±17 100±0 ns

Total RAI dose (mCi) 112±33 100±0 ns

Follow-up period (yr) 5.3±3.5 4.3±2.0 ns

Recurrence (no.) 1 2 ns

RAI: radioiodine; TNM: tumor node metastases classification.

Patients without recurrence Patients with recurrence p(no. 114) (no. 17)

Female/male (no.) 92/22 14/3 ns

Initial treatment (no.)Surgery 24 4 nsSurgery+RAI 90 13

TNM-T (no.)T1 34 1 <0.05T2, T3, T4 80 16

TNM-N (no.)N0 92 10 <0.05N1 22 7

Multifocality (no.) 26 2 ns

Vascular invasion (no.) 25 5 ns

Soft tissue invasion (no.) 32 7 ns

Initial RAI dose (mCi) 113±22 90±51 <0.01

Total RAI dose (mCi) 113±22 31±169 <0.001

NS: not significant; RAI: radioiodine; TNM: tumor node metastases classification.

Table 2 - Study parameters of papillary microcancer (PMC) patients with and without incidental tumor.

Table 3 - Study parameters of patients with and without recurrences.

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The presence of lymph node metastases at initial pre-sentation had near significant effect on disease-free sur-vival. Disease-free survival of patients with initial lymphnode metastases at 10 yr was 53% compared with pa-tients without initial lymph node metastases (78%, LongRank: 3.8, p=0.05) (Fig. 1).In addition, disease-free survival did not differ signifi-cantly in PC and PMC patients (data not shown).

DISCUSSION

The main finding of our study is that the presence oflymph node metastases at initial presentation may predictrecurrence/metastases during follow-up in patients withpapillary thyroid cancer. Although previous studies indi-cated lack of a significant negative effect of initial lymphnode metastasis on disease-free survival and/or recur-rence (3-6), a number of studies indicated the opposite,supporting our results (1, 2, 7-13). Shah et al. (3), indi-cated that regional lymph node metastases pointed to afavorable prognosis. Cady et al. (4) reported that patientswith lymph node metastases had a lower mortality ratecompared with patients without nodal involvement, in-dicating that increased number of nodal metastases (>10)led to better survival. Lerch et al. (5) evaluated signifi-cance of lymph node metastases in 464 patients with dif-ferentiated thyroid carcinoma; showing no effect oflymph node metastases on survival by multivariate anal-ysis. Mazzaferri et al. (7) and Dean et al. (8) reported thatpresence of initial lymph node metastases had no effecton mortality but was associated with increased risk of re-currence. More recently Mazzaferri et al. (2) reported that

initial lymph node metastasis was an independent vari-able for distant metastasis and cancer mortality (hazardratios 1.6 and 2.0, respectively), supporting the results ofa population study from Norway (9). Scheuman et al. (10),reported that lymph node metastases at presentation sig-nificantly affected recurrence and survival in patients withT1-3 tumors. Pellegriti et al. (13) indicated that presence of initial lymphnode metastases was associated with increased risk ofdistant metastases in 299 patients with papillary thyroidcarcinoma <1.5 cm. In their study, persistent/recurrentdisease in 299 patients with PC<1.5 cm, was associatedwith non-incidental cancer, presence of lymph nodemetastases at presentation and bilateral tumor, lymphnode metastases at presentation being the strongest pre-dictor of persisting/relapsing disease (odds ratio: 4.49).More recently Lundgren et al. (11) reported that patientswith lymph node metastases have an increased risk ofdeath compared with patients without lymph nodemetastases even after adjusting for TNM stage (odds ra-tio: 1.9). Although no mortality was observed during fol-low-up in our patients, presence of initial lymph nodemetastases is associated with increased recurrence ratio(odds ratio: 3.15 according to univariate analysis) andpredicts shorter disease free survival in our study. Leboulleux et al. (14), indicated that in 148 consecutivepatients with papillary thyroid cancer, significant risk fac-tors for persistent disease were lymph node metastases>10 lymph node, lymph node metastases with extracap-sular extention >3 lymph node, tumor size >4 cm andpresence of central lymph node metastases. Rouxel etal. (15) reported that factors significantly associated with

Variables Univariate Multivariate

Age p=0.25, OR=1.75 (0.66-4.67) p=0.09, HR=2.42 (0.85-6.94)>45 (no.=70)≤45 (no.=61)

Gender p=0.38, OR=0.60 (0.19-1.88) p=0.40, HR=0.58 (0.16-2.08)Male (no.=25)Female (no.=106)

Patients from p=0.33, OR=0.61 (0.22-1.66) p=0.33, HR=1.73 (0.57-5.28)Endemic region (no.=71)Non-endemic region (no.=60)

TNM-T at presentation p=0.02, OR=4.02 (1.01-6.11) p=0.52 HR=2.09 (0.72-6.93)T1 (no.=35)T2, T3 T4 (no.=96)

TNM-N at presentation p=0.02, OR=3.15 (1.12-8.80) p=0.16 HR=2.24 (0.61-1.77)N0 (no.=102)N1 (no.=29)

Vascular invasion p=0.70, OR=1.21 (0.40-3.78) p=0.58 HR=1.52 (0.34-6.82)Present (no.=30)Absent (no.=101)

Soft tissue invasion p=0.20, OR=1.90 (0.69-5.16) p=0.48, HR=1.62 (0.34-6.28)Present (no.=39)Absent (no.=92)

Multifocality p=0.52, OR=0.65 (0.17-2.42) p=0.54, HR=1.50 (0.38-5.81)Present (no. 28)Absent (no. 103)

Initial treatment p=0.97, OR=1.02 (0.31-3.36) p=0.64, HR=1.43 (0.30-6.77)Surgery (no.=28)Surgery+RAI (no.=103)

RAI: radioiodine; OR: odds ratio; HR: hazard ratio; TNM: tumor node metastases classification.

Table 4 - The prognostic value of the variables for recurrence Cox proportional hazard model.

O. Soyluk, F. Selcukbiricik, Y. Erbil, et al.

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a reduced survival and related to initial tumor in 172 pa-tients with loco-regional recurrences of differentiated thy-roid cancer were age ≥45 yr, follicular histology, and pres-ence of thyroid capsular effraction. In our study, age andpresence of thyroid capsule invasion had no effect ondisease-free survival. In our patients no mortality was observed during follow-up, but relatively shorter follow-up period for papillarythyroid cancer in our patients should be considered. Re-currence ratio was found as 12.9%. This ratio is similar topreviously reported ratio of 5-20% for local recurrence(1), but lower than those reported by Pellegriti et al. (13)and Mazzaferri et al. (2) (25.7% and 35%, respectively).Although the sample size is relatively small, patients withPMC had recurrence ratio comparable to patients withtumor >1 cm. Patients with microcancer had significant-ly shorter follow-up interval compared with patients withtumor ≥1 cm. Increased diagnosis of PMC in recent yearsmay be responsible for this observation. In addition, theage of PMC patients were significantly older. PMC pa-tients with incidental tumor (no.=33) underwent thy-roidectomy at a relatively older age because of the pres-ence of multinodular goiter.Remnant ablation significantly reduced 10-yr risk of lo-co-regional recurrences and distant metastases accordingto a recent analysis (16). In our study, patients with re-current tumor had relatively lower initial doses of 131Itreatment. Although higher doses of 131I are associatedwith lower recurrences, it is difficult to conclude that high-er doses of 131I are more effective in preventing recur-rences because of the retrospective design of our study.Larger group of patients should be followed-up forlonger periods of time in a prospective design to clearlyanswer this question. Mazzaferri et al. (17) indicated lowdose 131I (29-50 mCi), was as effective as high-dose 131I(51-200 mCi) for the prevention of recurrences. In our study, age at presentation had no significant ef-fect on survival. Pellegriti et al. (13) reported a similarfinding. In their series age had no effect on recurrence.These findings are in contrast with previous reports (1-4,

6, 7, 9, 12, 15, 18), indicating older age is associated withincreased risk of recurrence and decreased survival.In our study, patients with an initial tumor stage of >1had increased recurrence ratio. Cox univariate regressionanalysis indicated significantly increased risk of recurrencewhen initial tumor stage >1. Several studies also indicat-ed tumor diameter as a prognostic factor for recurrence(1-3, 7, 11, 12, 14). Pelizzo et al. (18), recently indicatedthat in multivariate analysis, age at presentation, extent ofdisease, extent of surgery, and presence of 131I-positivemetastases are significant and independent prognosticfactors in 1858 patients with papillary thyroid cancer. Limitations of our study are small sample size, its retro-spective design and relatively short follow-up period todetect recurrences. Although papillary thyroid cancer car-ries excellent prognosis in general, some patients devel-op recurrence/metastases during follow-up. Initial char-acteristics may identify high-risk subgroup of patients.According to our results, presence of lymph node in-volvement at presentation should lead to more vigoroustreatment approach and closer follow-up both in patientswith tumor diameter ≥1 cm and <1 cm.

Cum

ulat

ive

surv

ival

1.2

1.0

0.8

0.6

0.4

0.2

0.0

–0.20 10 20 30

Follow-up time

Survival function

Initial lymph node

N1N0

Fig. 1 - Recurrence-free survival accord-ing to the presence of initial lymph nodemetastasis.

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