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10.1245/s10434-006-9207-5
Annals of Surgical Oncology 14:730-738 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Prognostic Factors in Papillary and Follicular Thyroid Carcinoma: Their Implications for Cancer Staging

Brian Hung-Hin Lang, MBBS, FRACS1, Chung-Yau Lo, MS, FRCS (Edin), FACS1, Wai-Fan Chan, MBBS, FRCS1, King-Yin Lam, MD, FRCPA2 and Koon-Yat Wan, MBBS, FRCR3

1 Division of Endocrine Surgery, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China
2 Discipline of Pathology, School of Medicine, Griffith University, Gold Coast, Australia
3 Department of Clinical Oncology, University of Hong Kong Medical Centre, Queen Mary Hospital, Pokfulam road, Hong Kong SAR, China

Correspondence: Address correspondence and reprint requests to: Chung-Yau Lo, MS, FRCS (Edin), FACS; E-mail: cylo{at}hkucc.hku.hk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are two distinct histological types of thyroid carcinoma but have often been studied and staged as a collective group, known as differentiated thyroid carcinoma (DTC). However, this may not be an optimal approach to cancer staging.

Methods: A total of 760 patients with DTC, comprising 589 (77.5%) with PTC and 171 with (22.5%) FTC, being managed at our institution from 1961 to 2001 were retrospectively reviewed. Their clinicopathological features, treatment modalities received, and postoperative outcome were analyzed. Both univariate and multivariate analyses were performed to identify prognostic factors related to cancer-specific survival (CSS) for PTC and FTC.

Results: There were statistically significant differences between PTC and FTC in terms of age ≥50 years at diagnosis (P = .040), tumor size (P < .001), lymph node metastases (P < .001), distant metastases (P < .001), extrathyroidal extension (P < .001), multifocality (P = .002), capsular invasion (P < .001), extent of thyroid resection (P < .001), radioiodine ablation (P < .001), and external-beam irradiation (P = .003). Although PTC and FTC had similar 10-year and 15-year CSS (P = .846), each possessed its own set of independent prognostic factors for CSS. Age at diagnosis and completeness of resection were independent prognostic factors in both PTC and FTC.

Conclusions: There were marked differences in clinicopathologic features, treatment, and prognostic factors between the two histologic types of DTC. Different staging systems should be evaluated and validated for PTC and FTC individually in the future.

Key Words: Prognostic factors • Differentiated thyroid carcinoma • Papillary thyroid carcinoma • Follicular thyroid carcinoma • Staging • Risk stratification


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Differentiated thyroid carcinoma (DTC) accounts for at least 90% of all follicular cell–derived thyroid malignancies and comprises two distinct histological types, namely papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC).1 In our locality, its incidence has increased by 2.5-fold over the last 20 years,2 and a similar trend had also been observed overseas.3–6 Although the prognosis of DTC is generally regarded as favorable, up to 10% of patients will eventually die of the disease.1,7,8 As a consequence, a number of studies have identified various clinicopathological prognostic factors in DTC and devised risk-group stratification, staging methods, and scoring systems to facilitate treatment strategy.9–26 When it comes to cancer staging for DTC, it is not an uncommon practice to stage PTC and FTC together as a group with the same set of staging system for risk-group stratification, but it is questionable whether this is entirely appropriate for cancer staging and predicting cancer-specific survival (CSS). However, to our knowledge, all of the currently available staging systems were derived specifically from patients with DTC,11,15,18,19,21,26 PTC,10,12–14,16,17,22,25 or all types of thyroid carcinoma,9,20,23,24 and not from patients with FTC only. Furthermore, none of the existing systems have been shown to be consistently superior in predicting CSS for PTC, FTC, or DTC, although a comparison of staging systems has previously been attempted for individual type of DTC.27–30 The present study aimed at identifying the prognostic factors for CSS in PTC and FTC separately on the basis of the current available staging or classification systems and finding out their implications in cancer staging for PTC and FTC.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Patients
From 1961 to 2001, a total of 760 consecutive patients with a histologic diagnosis of DTC who underwent primary surgical treatment at our institution were recruited onto the present study. Most patients were female (80.5%) and ethnic Chinese (93.7%). The median age of the entire cohort was 43.0 years (range, 10.0–89.0 years). There were 589 patients with PTC (77.5%) and 171 patients with FTC (22.5%). All histological variants of PTC (n = 170, 22.4%) and FTC such as Hürthle cell carcinoma (n = 22, 2.9%) were included. The most common nonclassical PTC variants were follicular (n = 73, 9.6%), encapsulated (n = 31, 4.1%), and tall cell (n = 23, 3.0%) variants. The incidence of microcarcinomas (tumor size ≤1.0 cm) in PTC and FTC were 18.8% and 8.8%, respectively. To ensure consistency and accuracy, each histologic diagnosis was reconfirmed after a careful review of the retrieved slides by a dedicated pathologist (K.Y.L.) who was unaware of the clinical data, according to the standardized criteria approved by World Health Organization.31

Surgical Treatment and Adjuvant Therapy
For those patients with a preoperative diagnosis of DTC, a total or near-total thyroidectomy (as defined as leaving <1 g of thyroid tissue behind) has increasingly been the preferred procedure. For those diagnosed after a lobectomy, the decision of whether to perform a completion total thyroidectomy and/or to administer radioiodine (RAI) ablation afterward was determined by known risk factors such as the patient’s age and tumor characteristics, as well as patient preference. If patients underwent completion total thyroidectomy within 6 months of their initial thyroid surgery, it was considered as part of initial surgery. However, if reoperations were performed for residual or nodal disease 6 months after diagnosis, it was considered to be locoregional recurrence. Routine palpation and sampling of enlarged or suspicious lymph nodes in the central and lateral compartments were performed at the time of operation and were supplemented with the more frequent use of preoperative ultrasonography of the neck with or without fine-needle aspiration cytology. A selective neck dissection, as defined as the clearance of cervical lymph nodes in levels II to V while preserving internal jugular vein and accessory nerve, was performed for cytologically or histologically proven lateral lymph node metastasis. Incomplete resection was defined as residual tumor left behind, as judged by the operating surgeons.

Patients with at least one or more of the following risk factors would be considered for RAI ablation 4 to 6 weeks after surgical treatment by T4 withdrawal: tumor size >1 cm, lymph node metastasis, age >40 years, presence of extrathyroidal extension, incomplete resection, and distant metastasis. Diagnostic whole-body 131I scans were performed 8 to 12 weeks after RAI therapy. Three gigabecquerels (GBq; 80 mCi) of 131I would be administered as standard ablative dose, whereas subsequent 131I therapy would be performed at 5.5 (GBq; 150 mCi). Additional 5.5 GBq 131I therapy would be administered periodically at 4- to 6-month intervals until uptake was no longer visible or disease progressed despite treatment. External local radiotherapy would be provided to patients with extensive extrathyroidal tumor extension, incomplete resection, and/or extracapsular lymph node metastasis. Although the above protocol was strictly followed, individual patients’ preference were considered and respected.

Follow-up and Surveillance of Patients
Complete follow-up data were available for all patients. The median follow-up period for the whole patients’ cohort was 118 months (range, 60–497 months). Patients with PTC were followed over a median period of 93 months (range, 60–497 months), whereas those with FTC were followed over a median period of 119 months (range, 72–488 months). All patients after surgery were followed within 4 weeks in a specialized combined surgical oncology clinic where clinical oncologists and endocrine surgeons were present to discuss and decide on subsequent management. Follow-up visit was conducted once every 3 months in the first 2 years, once every 6 months for the next 3 years, and annually thereafter. Clinical examinations, chest x-ray, and ultrasonography of neck were performed and thyroglobulin levels (since 1989) determined during follow-up visits. Radioactive scans were performed in the presence of increased thyroglobulin level, documented nodal recurrence, or radiological evidence of recurrence or metastases. Human recombinant thyroid-stimulating hormone was not available during the study period at our institution.

The diagnosis of distant metastases at presentation was based on findings of histological, radiological, or scintigraphic evidence and was not based on increased thyroglobulin level only. Locoregional recurrences were frequently diagnosed by ultrasound, computed tomography, or magnetic resonance imaging and confirmed by fine-needle aspiration cytology. Survival data, including the cause of death, were retrieved from the Hong Kong Hospital Authority territory-wide computerized medical system and from death certificates or postmortem examinations. The present study protocol was approved by the appropriate institutional review committee in accordance with the precepts established by the Declaration of Helsinki in 2000.

Statistical Analysis
Survival was calculated from the date of initial surgery to the date of death or last follow-up. The end point for the present analysis was CSS, which was defined as a known cause of death from meta-static or recurrent thyroid carcinoma. Like most existing staging systems, continuous variables such as age and tumor size were transformed into dichotomous variables. A single best cutoff point for each continuous variable was determined by the receiver operating characteristic curve and Youden’s index. The {chi}2 test or Fisher’s exact test was used for comparison of dichotomous variables and the Mann-Whitney U-test for continuous variables between PTC and FTC. For each histological type, potential clinicopathological risk factors were evaluated by univariate analysis, and those that had a significance level of P < .05 were entered into the multivariate analysis. A multivariate Cox proportional hazard regression model with a backward stepwise elimination procedure was then carried out to identify independent factors and their regression or ß-coefficients. A ß-coefficient of zero implied that the independent factor was not a predictor of cancer-related mortality. A positive value implied an association with cancer-related mortality, and a larger value implied a stronger predictor of cancer-related mortality. Analysis was performed by SPSS 11.0 statistical package for Windows (SPSS, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
From the receiver operating characteristic curve analysis, the optimal cutoff point for age at diagnosis and tumor size in PTC were 49.5 years (P < .001 area under the curve [AUC] = 81.4% with 95% confidence interval [95% CI] = 75.4–87.4, and Youden’s index = .524 with sensitivity 84.0% and specificity 68.4%) and 3.5 cm (P < .001, AUC = 68.3% with 95% CI = 59.5–77.1, and Youden’s index = .323 with sensitivity 56.5% and specificity 75.8%), respectively. In FTC, the optimal cutoff point for age at diagnosis and tumor size were 52 years (P < .001, AUC = 82.4% with 95% CI = 74.3–90.6, and Youden’s index = .588 with sensitivity of 90.9% and specificity of 67.9%) and 3.8 cm (P = .479, AUC = 55.1% with 95% CI = 38.7–71.4, and Youden’s index = .241 with sensitivity of 27.8% and specificity of 96.3%). For convenience, the cutoff point for age and size in both histologic types were taken as 50 years and 3.5 cm, respectively.

The clinical characteristics of PTC and FTC patients were compared (Table 1Go). In terms of patient demographics, there was no difference in the proportion of female sex in both histologic types. The median age at presentation in patients with PTC was 43.0 years (range, 10.0–89.0 years), whereas in FTC, it was 45.0 years (range, 13.0–87.0 years); this was not significantly different (P = .586). However, there was a greater proportion of FTC patients with age ≥50 years (P = .040) and tumor size ≥3.5 cm (P < .001) at presentation. In addition, the median tumor size was significantly larger in FTC when compared with PTC (3.0 vs. 2.0 cm, P < .001).


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  		TABLE 1. Comparison of clinicopathologic characteristics and treatment modalities between papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC)
 
On further analysis, the proportion of tumors with size <1 cm was significantly higher in PTC than FTC (10.5% vs. 4.7%, P = .010). The incidence of lymph node metastases was significantly higher in PTC than FTC (41.9 vs. 7.0%, P < .001). On the other hand, distant metastases at presentation was significantly higher in FTC than PTC (11.1 vs. 1.7%, P < .001). Despite the smaller tumor size, the incidence of extrathyroidal extension and tumor multifocality were significantly higher in PTC than FTC (62.0 vs. 9.4% and 32.6 vs. 20.5%, respectively; P < .001 and P = .002, respectively). On the other hand, invasion into tumor capsule was more commonly seen in FTC (78.9 vs. 31.4%, P < .001). In terms of treatment received, bilateral thyroid resection was more readily performed in PTC (90.2 vs. 80.7%, P < .001), but RAI ablation was more commonly administered in FTC after definitive surgery (66.7 vs. 60.8%, P < .001). External-beam irradiation was more frequently administered for PTC than FTC (12.7 vs. 5.3%, P = .003).

Survival
The CSS rate for the entire patient cohort at 5, 10, and 15 years was 94.7%, 90.5%, and 87.9%, respectively. Figure 1Go compares the estimated CSS for patients with PTC and FTC. The CSS for patients with PTC and FTC at 5, 10, and 15 years were 95.1%, 91.3%, and 87.7% and 93.2%, 88.2%, and 88.2%, respectively. There was no significant difference in CSS between the two histologic types (P = .867). Even when tumors with size <1 cm were excluded from the survival analysis, there was still no significant difference in CSS between the two histologic types (P = .779). A total of 129 deaths occurred to date, with 67 from thyroid carcinoma, 22 from nonthyroidal malignancy, and 40 from concomitant medical illness. Confirmation of cause of death was supported by postmortem examination in 29 cases, and the remaining cases were based on death certificate reports. In terms of tumor recurrences, 78 patients with DTC developed recurrence but were rendered disease-free after treatments with a median follow-up of 181 months (range, 72–419 months), whereas 27 were alive with recurrence with a median follow-up of 74 months (range, 69–113 months). A total of 121 and 36 patients had locoregional and distant recurrences, respectively. Twenty-three patients had both loco-regional and distant recurrences.


Figure 1
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  		FIG. 1. Estimated cancer-specific survival curves by Kaplan-Meier method for papillary thyroid carcinoma (PTC) (broken line) and follicular thyroid carcinoma (FTC) (solid line).

 
Univariate Analysis
Univariate analysis was performed to find potential risk factors predicting CSS for patients with PTC (Table 2Go). Age ≥50 years at diagnosis was associated with a worse CSS (P < .001). Other significant predictors for a worse CSS in the univariate analysis included tumor size ≥3.5 cm (P < .001), lymph node metastases (P = .019), distant metastases (P < .001), extrathyroidal involvement (P < .001), multifocal tumors (P = .048), capsular invasion (P < .001), and incomplete resection (P < .001). Sex was not a significant predictor of CSS. Although follicular PTC was not associated with a worse CSS when compared with the classical PTC, the tall cell variant of PTC was associated with a worse CSS (P = .038).


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  		TABLE 2. Univariate Cox regression analysis of clinicopathologic variables and treatment modalities in papillary thyroid carcinoma (PTC)
 
Treatment modalities were also assessed to identify any potential effect on the outcome. A less extensive thyroid resection (i.e., subtotal thyroidectomy and lobectomy) was associated with a lower hazard ratio when compared with total thyroidectomy, although it did not significantly influence the overall CSS. The lower hazard ratio may be related to a selection bias because patients with higher risk tumors were more likely to be selected for total thyroidectomy. Similarly, administering external-beam irradiation to neck was associated with a worse CSS, partly because >60% of these patients had incomplete resection or macroscopic residual disease, which itself was an adverse prognostic predictor of CSS in the univariate analysis.

Table 3Go shows the univariate analysis of potential risk factors predicting CSS for patients with FTC. Similar to PTC, age ≥50 years at diagnosis was associated with a worse CSS (P < .001). Other significant factors for a worse CSS in the univariate analysis included the presence of distant metastases (P < .001), widely invasive histology (P = .017), and incomplete resection (P < .001). Multifocality had a marginally significant P value of .092 and so was included in the multivariate analysis. Sex, tumor size, lymph node metastases, extrathyroidal extension, capsular invasion, and angioinvasive FTC were not statistically significant predictors for CSS in the univariate analysis. Similar to PTC, a less extensive thyroid resection was associated with a hazard ratio of <1, but the P value did not reach significance. Radioiodine ablation did not influence CSS, but external-beam irradiation to the neck was associated with a worse CSS (P < .001).


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  		TABLE 3. Univariate Cox regression analysis of clinicopathological variables and treatment modalities in follicular thyroid carcinoma (FTC)
 
Multivariate Analysis
Individual multivariate analysis of CSS in patients with PTC and FTC was performed (Table 4Go). There were four independent predictors for PTC and three independent predictors for FTC. Age at diagnosis and completeness of resection were the only two common independent predictors (P < .05) for both PTC and FTC. Tumor size (P = .003) and extra-thyroidal extension (P = .020) were independent predictors of CSS in PTC, whereas distant metastases (P = .001) was an independent predictor of CSS in FTC. In PTC, lymph node metastases, multifocality, capsular invasion, tall cell variant of PTC, and external-beam irradiation did not independently affect CSS. In FTC, multifocality, widely invasive FTC, and external-beam irradiation did not independently affect CSS.


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  		TABLE 4. Results of multivariate analysis for cancer-specific survival in papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC)
 
On the basis of the magnitude of the ß-coefficient in the multivariate analysis, age ≥50 years at diagnosis seemed to be the most dominant independent predictor of CSS in PTC. The other three independent predictors had ß-coefficient values of <1. In FTC, although age at diagnosis still had the highest ß-coefficient value (2.82) in multivariate analysis, the other two independent predictors—distant metastases and completeness of resection—had ß-coefficient values of 1.66 and 2.38, respectively.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
PTC and FTC are the two most prevalent histological types of thyroid carcinoma and are often collectively referred to as DTC. They have often been studied together because of convenience and because they originate from the same progenitor cell. Both histological types had initially demonstrated similar biologic behavior and prognosis.32–34 However, there is increasing evidence to suggest that the two histologic types should be analyzed separately because of their differences in clinical and biologic behaviors.35–39 The exact reason for the recent recognition of these differences between PTC and FTC remains uncertain, but it may be related to longer follow-up of patients with DTC and to clearer histological definitions in FTC and other follicular lesions of the thyroid gland in general.40,41 Nevertheless, our results would support the latter recommendation because despite the remarkably similar CSS between PTC and FTC in our series, there were marked differences in clinicopathologic features and treatment approaches between these two types of thyroid carcinoma. When compared with FTC, patients with PTC tended to present at age <50 years at diagnosis, have smaller tumors, and be associated with a higher incidence of lymph node metastases, extrathyroidal extension, and multifocality at presentation. However, the incidence of capsular invasion and distant metastases were lower in patients with PTC when compared with patients with FTC. Our comparison also showed that there were statistically significant differences in treatment received between the two histologic types, despite having similar treatment protocol. Total thyroidectomy was more readily performed, external-beam irradiation was more frequently performed, and RAI ablation was less frequently administered for patients with PTC compared with FTC. These differences in patient characteristics and treatment approaches agreed with and confirmed the findings of reports from other authors.35–39,42

From our univariate and multivariate analyses, it was clear that both PTC and FTC possessed a different set of prognostic factors affecting CSS. This finding was consistent with that of a recent collective study on PTC and FTC.42 Interestingly, in that particular study, distant metastases and tumor size, but not age, were found to be statistically significant independent factors of FTC. Although our results showed that both age at diagnosis and completeness of resection were statistically significant independent predictors for both PTC and FTC, other important independent prognostic predictors, such as tumor size, extrathyroidal extension, and distant metastasis, were specific to PTC or FTC only. If DTC were analyzed in a multivariate analysis as a group, it might not have been possible to appreciate the subtle differences in prognostic factors between the two histologic types. We believed that there might be a potential drawback seen in some studies where PTC and FTC were collectively analyzed as a group. One potential problem with this type of analysis is that PTC is far more common and at times outnumbers FTC by a ratio of 4:1, and so the results obtained from the Cox proportional regression analysis would be skewed toward PTC rather than FTC, and less dominant independent predictors in FTC may be overshadowed by those in PTC.

Implications for Cancer Staging
Prognostic factors form the basis of cancer staging,43 and so evaluating these factors from the survival analysis would provide valuable insights into the way cancer should be staged in our patient cohort. There are several deductions that could be made from our multivariate analyses. First, regardless of the histologic type, age ≥50 years at diagnosis was the single most powerful independent prognostic factor in our series. Given that age was a dominant prognostic factor in both PTC and FTC, any staging systems with age as a criterion would naturally predict CSS to an extent regardless of the histologic type. Of course, the age criterion may vary among staging systems and may differ from our cutoff point of 50 years, but most systems that included age as a criterion had set their cutoff point in the vicinity of 50 years.10,11,13,14,17,18,20–26 This implies that as long as an appropriate age cutoff point is set in a staging system, as most had done, it would be possible to stratify PTC, FTC, or DTC at least into low- or high-risk groups. Interestingly, a recent study demonstrated just this by incorporating only two variables (age 50 years and extrathyroidal extension) into a simplified staging scheme and found that it could stratify low- and high-risk tumors well; in addition, the predictability of the new scheme seemed to be comparable to the other, more established systems such as AGES, AMES, MACIS, TNM, and EORTC.43 This concept was further supported by the two comprehensive staging system comparisons, one based on a Canadian population and the other in an area in Austria with endemic goiters, illustrating that all the available staging systems with age as a criterion predicted CSS.27,28

Second, although age ≥50 years was the most powerful predictor of CSS as measured by the ß-coefficient value, its predictive power also depended on the coefficient value of the other independent factors. In PTC, the coefficient value of age ≥50 years almost equaled the sum of the other three coefficients put together (2.53 vs. 2.70). On the other hand, in FTC, the coefficient value of age ≥50 years was far less than the sum of the other two coefficients together (2.82 vs. 4.04). In relative terms, age seemed to be a less important predictor of CSS in FTC, mainly because of the dominance of other factors such as distant metastases and completeness of resection. This agreed with the findings of a recent study from Slovenia on FTC.44 Interestingly, some studies even found that age was not a risk factor for FTC at all; instead, they found that distant metastases were a more consistent independent predictor.42,45,46 However, further studies are required to confirm this finding.

Third, given that each histologic type possessed its own set of prognostic factors, it would seem reasonable that an optimal approach to cancer staging in DTC would be for each histologic type to be staged separately, with a different staging system if necessary. As previous studies have shown, a staging system that predicted survival well in one histologic type may not necessarily perform the same in another histologic type,20,27,28 and one would hope that the findings of the present study may have provided a plausible explanation on why this is so. On the basis of the current evidence available, the most applicable system may or may not have to be derived from patients with the same histologic type and may not necessarily be a new system.42,45,46 However, because the actual choice of staging system may vary with different medical centers depending on the referral pattern, treatment philosophy, and other less well-defined confounders, each center should evaluate, validate, and adopt the most predictive and applicable system for its own clinical use.47


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Despite their similar CSS, there were important differences in patient characteristics and treatment received between PTC and FTC. Patients with PTC tended to present at age <50 years, have smaller-sized tumors, and have a higher incidence of lymph node metastases, extrathyroidal extension, and multifocality. In our institution, they tended to receive more bilateral thyroid resections and more frequent external-beam irradiation to the neck. In contrast, FTC patients tended to have a higher incidence of distant metastases and capsular invasion, and to receive more frequent RAI ablation. Furthermore, this study showed distinctive differences in prognostic factors between the two entities: independent factors predicting poor prognosis for PTC were age ≥50 years, tumor size ≥3.5 cm, extrathyroidal extension, and incomplete resection; and for FTC, age ≥50 years, distant metastases, and incomplete resection. On the basis of these differences, it is perhaps appropriate to evaluate and validate different staging systems for the two histologic types of DTC individually rather than collectively in the future.

Received for publication July 10, 2006. Accepted for publication July 13, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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