July 1, 2007
Significance of Tumor Capsular Invasion in Well-Differentiated Thyroid Carcinomas
By Furlan, Julio C Bedard, Yvan C; Rosen, Irving B
This study examines the influence of tumor capsular invasion on the biological behavior of papillary (PTC) and follicular thyroid carcinoma (FTC) and the prognosis of surgically treated patients. This retrospective cohort study included 350 cases of PTC or FTC from a university teaching hospital. Patient charts were randomly selected and reviewed. The study population was divided into PTC and FTC groups. Each group was subdivided into CI+ (with tumor capsular invasion) and CI- subgroups (without tumor capsule or without capsular invasion). The long-term prognosis was assessed using the American Joint Committee on Cancer pTNM staging and the prognostic index was elaborated by the European Organization for Research and Treatment of Cancer. There were 284 women and 66 men (ages 19-89 years, mean of 44) with an incidence of 53.1 per cent for CI+ tumors. There were no significant differences between the PTC subgroups regarding the short-term clinical outcome and the long- term prognosis. Although patients with CI+ FTC showed lower incidence of lymph node metastasis than patients with CI- FTC, the FTC subgroups were comparable regarding the short-term clinical outcome and the long-term prognosis. Our results suggest that presence of tumor capsular invasion does not adversely influence biological behavior or survival of PTC or FTC. Moreover, the presence of tumor capsular invasion appears to not have significance for the long-term prognosis of patients with PTC or FTC. THYROID CANCER HAS been steadily increasing in Canada over the last three decades.1 The National Cancer Institute of Canada estimated 3100 new cases of thyroid cancer from which 170 deaths are expected in Canada in 2005.2 Canadian statistics also indicate that thyroid cancer has the highest increased incidence, whereas mortality from thyroid cancer decreased from the year 1993 to 2000. Generally speaking, this picture reflects the indolent course of papillary thyroid carcinomas (PTC) and follicular thyroid carcinomas (FTC), which are the most frequent histologie types of thyroid cancer (70%-80% and 10%-15%, respectively) with 10-year survival rates of approximately 90 per cent to 95 per cent and 70 per cent to 95 per cent, respectively.3,4
Unfortunately, some cases locally recur, and the cancers metastasize to locoregional lymph nodes and/ or distant organs and the patients die. Characterization of clinical and histologie features of PTC and FTC associated with adverse behavior has been a great challenge for scientists and clinicians. Several prognostic factors for PTC and FTC have been proposed such as age, sex, histology, tumor differentiation, size of the primary tumor, DNA euploidy, CD97, Ecadherin, telomerase activity, capsular invasion, and angioinvasion. However, there is little agreement on the importance of most of those clinical and morphologic variables on the prognosis of patients with PTC or FTC.4-5
This study was undertaken to examine the potential influence of presence of histologie tumor capsular invasion on the biological behavior of PTC and FTC, and to evaluate the prognosis for patients surgically treated for CI+ PTC or CI+ FTC in comparison with their respective CI- tumor counterparts.
Patients and Methods
This retrospective cohort study included 350 patients who underwent thyroidectomy for PTC or FTC from 1964 to 2000 at a university teaching hospital in Canada. Patient charts were randomly selected and reviewed. The study population was divided into PTC and FTC groups. Additionally, both groups were subdivided into patients with capsular invasive tumor (CI+ subgroup) and individuals with tumor without capsular invasion or without any tumor capsule (CIsubgroup). Therapeutic procedures were essentially selected based on demographics, clinical, and other histologic parameters, but not the presence or absence of tumor capsular invasion.
Data on demographics (age and sex), treatment features (extent of thyroidectomy, neck dissection, and adjuvant therapy), histopathological findings (lymph node metastasis, extrathyroidal invasion, angioinvasion, tumor size, and multicentricity), clinical outcomes (distant metastasis, recurrence, and postoperative elevated thyroglobulin level), and disease-free survival were collected for each subgroup of the FTC and PTC groups.
The diagnosis of PTC is essentially based on different features, including papillary architecture, psammona bodies, and cytologie characteristics.4 The differentiation between follicular thyroid adenomas and carcinomas depends on demonstration of angioinvasion and/or tumor capsular invasion.6
The patients were followed for a mean of approximately 4 years. Because that period of time is considered a short-term follow-up for PTC and FTC, we also estimated the long-term prognosis using the American Joint Committee on Cancer (AJCC) pTNM staging and the prognostic index elaborated by the European Organization for Research and Treatment of Cancer (E.O.R.T.C.; Table 1).7, 8
Data were analyzed using the chi-squared test, Fisher's exact test, Student's t test, and Mann-Whitney's rank sum test. In addition, the cumulative survival was estimated according to Kaplan- Meier and Cox regression analyses associated with log-rank test. All statistical analyses were carried out using SPSS software for Windows (version 11.0; SPSS, Chicago, IL). Significance was assumed at P
There were 350 patients (284 women and 66 men, age 19-89 years with a mean of 44.2 years) who underwent thyroidectomy for PTC (86%) or FTC (14%). Histologie tumor capsular invasion was present in 53.1 per cent in this series. Significantly higher incidence of CI+ tumors was observed in FTC (73.5%) than in PTC groups (49.8%; P = 0.003). There was no death related to thyroid cancer in this series.
Patients with PTC (245 women and 56 men, age 18-89 years with a mean of 44.3) were followed postoperatively for a mean of 41.9 months (1-420 months). There were no significant differences between CI+ PTC subgroup (n = 150) and CI- PTC subgroup (n = 151) with regard to age (44.1 +-1.3 years vs 44.5 +-1.2 years, respectively; P = 0.596) and sex distribution (82% men vs 80.8% women, respectively; P = 0.904).
TABLE 1. The AJCC Staging and the Prognostic Index from the E.O.R.T.C. for the PTC and FTC Thyroid Carcinomas
Patients with CI+ PTC were treated more radically than the CI- PTC subgroup with respect to extent of thyroidectomy and neck dissection, but there were no significant differences between the PTC subgroups for adjuvant therapy (Table 2). The short-term clinical outcome in the CI+ PTC subgroup was comparable with the CI- PTC subgroup (Table 2) after similar mean periods of follow-up (41.6 months vs 42.2 months, respectively; P = 0.831). There were no significant differences between the PTC subgroups for disease-free survival after treatment based on the Cox regression analysis (Fig. 1). Of note, disease-free survival reflects absence of recurrence, distant metastasis, and persistent postoperative elevated thyroglobulin level during the follow-up time.
Although both PTC subgroups showed similar incidences of tumor multicentricity and lymph node metastasis, the CI+ PTC subgroup had larger, more angioinvasive, and more locally invasive tumors than the CI- PTC subgroup (Table 3). There were no significant differences between the PTC subgroups for longterm prognosis based on the AJCC pTNM staging and E.O.R.T.C. prognostic index (Fig. 2).
There were 39 women and 10 men with FTC (ages 23-89 years with a mean of 43.2 years) who were postoperatively followed from 1 to 231 months (mean of 67.1 months). The CI+ FTC subgroup (n = 36) was similar to the CI- FTC subgroup (n = 13) with regard to age (44.7 +- 2.4 years vs 38.9 +- 2.9 years, respectively; P = 0.196) and sex distribution (80.6% men vs 76.9% women, respectively; P = 1).
TABLE 2. Treatment Features and Clinical Outcomes of the PTC Subgroups
FIG. 1. Disease-free survival in patients with tumor capsular invasive (CI+) and noninvasive (CI-) PTC. There was no significant difference between both PTC subgroups based on the log rank test (P = 0.388).
There were no significant differences between the FTC subgroups for extent of thyroidectomy and adjuvant therapy (Table 4). Of note, there was a trend for a higher frequency of neck dissection in the CI- FTC subgroup in comparison with the CI+ FTC subgroup, even though this did not reach significance (P = 0.061 ; Table 4). The CI+ FTC and CI- FTC subgroups had similar short-term clinical outcomes after comparable postoperative periods of follow-up (70.3 +- 11 months vs 58.4 +- 19.2 months; P = 0.408; Table 4). Using Cox regression analysis, no significant differences between the FTC subgroups were found with respect to disease-free survival after surgery (Fig. 3).
TABLE 3. Histopathological Findings of the PTC Subgroups
FIG. 2. Prognosis for the capsular invasive (gray bars) and noncapsule invasive (black bars) PTC subgroups based on the AJCC pTNM Staging (A) and the prognostic index from the E.O.R.T.C. (B).
There were no significant differences between the FTC subgroups with regard to tumor size, tumor multicentricity, extrathyroidal invasion, angioinvasion, and lymph node metastasis (Table 5). However, the CI- FTC subgroup showed a significantly higher incidence of nodal involvement than the CI+ FTC subgroup (23.1% vi 2.8%, respectively; P = 0.052). There were no significant differences in term of longterm prognosis between the FTC subgroups according to the AJCC pTNM staging and the E.O.R.T.C. prognostic index (Fig. 4). Discussion
The results of this retrospective cohort study suggest that the presence of histologic tumor capsular invasion may not adversely affect short-term clinical outcomes of patients with PTC or FTC. Of note, CI- FTC was associated with a higher incidence of lymph node metastasis than CI+ FTC. The presence of tumor capsular invasion does not appear to affect the longterm prognosis of patients with PTC or FTC based on the assessments using the AJCC pTNM staging and the E.O.R.T.C. prognostic index. Those results suggest that presence of tumor capsular invasion is not a significant independent factor for morbidity or mortality related to the cancer.
Diagnosis of Tumor Capsule Invasion
The identification of tumor capsular invasion in the FTC has received more attention than in the PTC because the differentiation between follicular adenomas and carcinomas relies on the demonstration of angioinvasion and/or tumor capsular invasion.6 More specifically, the latter raises issues concerning the interobserver and intraobserver reliability because the criteria for tumor capsular invasion are not always easily applicable.9 Analyzing follicular neoplasms of the thyroid gland, Lang et al.10 demonstrated the importance of sampling the tumor because the diagnosis of cancer is directly correlated, in a linear fashion, to the number of tissue blocks that are examined. Using a three- dimensional reconstruction model for tumor tissues and capsules from serial sections, Aida et al.11 reported that most capsule invasion in FTC may not be true invasion. Therefore, demonstration of capsular invasion is sometimes technically difficult, which may bias the analysis on the influence of capsular invasion on the post- treatment outcome of patients with PTC or FTC.
TABLE 4. Treatment Features and Clinical Outcomes of the FTC Subgroups
FIG. 3. Disease-free survival in patients with tumor capsular invasive (CI+) and noninvasive (CI-) FTC. There were no significant differences based on the log rank test (P = 0.175).
Significance of Tumor Encapsulation
The presence of histologic capsule invasion was observed in approximately half of our study population, with a higher incidence in FTC (73.5%) than in PTC (49.8%). The remaining cases had no tumor capsule or the capsule was not invaded by the tumor. This finding is comparable with previous studies that reported the absence of tumor capsule in 10.3 per cent to 50 per cent of PTC and FTC.12-15 The tumor encapsulation was associated with reduced patient survival in a univariate analysis by Besic et al.,16 even though tumor encapsulation was not confirmed as an independent prognostic factor in the multivariate analysis. Akslen et al.13 showed that absence of tumor capsule had no impact on prognosis of patients with PTC whatsoever. Evans17 also found that thyroid neoplasms with tumor capsule associated with cytological characteristics of PTC without invasion showed benign behavior during a minimum period of follow- up of 10 years. Mirallie et al.14 reported that absence of tumor capsule was a predictive factor for node involvement in patients with PTC. Carcangiu et al.18 demonstrated that lymph node metastasis was more frequent in patients with nonencapsulated PTC than patients with encapsulated PTC.
A similar relationship between tumor encapsulation and clinical outcome has been reported in studies on cancers from other sites. The presence of tumor capsule was associated with good prognosis in hepatocellular carcinomas and liver metastasis from colorectal cancer.19 Accordingly, it was hypothesized that the capsular formation serves as a mechanical and chemical barrier to local invasion by malignant cells.19
Significance of Tumor Capsular Invasion
Our results demonstrated that the presence of tumor capsule invasion was associated with larger, more locally invasive, and angioinvasive tumors in the PTC group at diagnosis. There was no significant association of presence of tumor capsule invasion with tumor size, tumor multicentricity, extrathyroidal invasion, and angioinvasion in individuals with FTC at diagnosis. In our study, short-term clinical outcome was unaffected by the presence of tumor capsule invasion in patients with PTC or FTC during the mean follow- up time of approximately 4 years. Also, there were no significant differences between patients with CI+ PTC and CI- PTC with regard to disease-free survival. Similarly, patients with CI+ FTC had similar freedisease survival than patients with CI- FTC in our study.
TABLE 5. Histopathological Findings of the FTC Subgroups
FIG. 4. Prognosis for the capsular invasive (gray bars) and noncapsule invasive (black bars) FTC subgroups based on the AJCC pTNM Staging (A) and the prognostic index from the E.O.R.T.C. (B).
Previous studies also indicated that tumor capsular invasion is not a predictive factor of recurrence after complete ablation for well-differentiated thyroid carcinoma.20 Van Heerden et al.6 reported that FTC that was diagnosed on the basis of presence of tumor capsule invasion alone behaves in a benign fashion without distant metastasis or death related to the cancer. Besic et al.16 reported that the presence of tumor capsule invasion appears to be significantly associated with reduced patient survival in a univariate analysis, but this was not confirmed by multivariate analysis. Nonetheless, widely invasive FTC has been associated with a higher incidence of morbidity, including distant metastases and local recurrence, and mortality in numerous investigations.12, 21- 23 Zidan et al.24 reported that more patients had tumor capsular invasion and less nodal involvement in follicular variant of PTC than patients with pure PTC. A number of previous studies reported that patients with minimally invasive FTCs, characterized by evidence of a focal and superficial angioinvasion and/or tumor capsule invasion, had good clinical outcomes and excellent long- term prognosis.21, 22, 25, 26 Other studies demonstrated that recurrence, distant metastasis, and mortality were not significantly correlated with the extent of tumor capsule invasion.27,28
In our study, there were no significant differences between CI+ PTC and CI- PTC for prognosis using the AJCC pTNM staging and E.O.R.T.C. prognostic index. Similarly, there were no significant differences between CI+ FTC and CI- FTC with respect to prognosis using the AJCC pTNM staging and E.O.R.T.C. prognostic index.
One potential limitation of our study is the shortterm follow-up for most of the cases. This is a common problem of several retrospective studies that may limit their conclusions in terms of external validity. In reality, the need for follow-up time of minimum of 10 years makes it almost unfeasible for prospective studies focused on well-differentiated studies. Given those limitations, we sought to evaluate the long-term prognosis using the AJCC pTNM staging and E.O.R.T.C. prognostic index. Although several classifications with different variables have been developed to define risk groups of thyroid cancer, only few prognostic scoring systems have been proved as reliable predictors of survival in different populations.5, 29-33 The AJCC pTNM staging and E.O.R.T.C. prognostic index have been used in FTC and PTC, even though there are some potential limitations in terms of generalizability and reliability.7,8-29
Another important limitation inherent in our retrospective cohort study refers to the difficulty of precisely classifying FTC in different degrees of capsular invasiveness as characterized in previous studies. 12,21-23 jnuSi we cannot rule out that widely invasive FTC is more aggressive than minimally invasive FTC. Moreover, we were unable to compare the pathological, clinical, and prognostic characteristics of patients with widely invasive PTC with patients with FTC without tumor capsular invasion or patients with FTC without tumor capsule. Finally, we could not precisely distinguish patients with tumor capsule without invasion from patients without tumor capsule in the PTC and FTC groups based on the tissue reports.
Our results suggest that the presence of tumor capsule invasion is a histopathological finding without significance for the short- term clinical outcome or for the long-term survival of patients with PTC or FTC. However, CI+ PTC was associated with tumors with larger size, more frequent local invasion, and more often vascular invasive in our study. The absence of tumor capsule invasion or the absence of tumor capsule appears to be suggestive of susceptibility for nodal involvement in cases of FTC. Further investigation is required to confirm those suggestions.
We thank Mrs. M. Alien for her assistance with the preparation of this manuscript. This study was supported by a grant from The Head and Neck Cancer Foundation.
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JULIO C. FURLAN, M.D., M.B.A., PH.D.,*t YVAN C. BEDARD, M.D., M.D.,[double dagger] IRVING B. ROSEN, M.D.*
From the *Oepartment of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada;
the [dagger] Department of Surgery, Division of Neurosurgery, Toronto Western Hospital, University of Toronto,
Toronto, Ontario, Canada; and the [double dagger] Department of Laboratory Medicine and Pathobiology, Mount Sinai
Hospital, University of Toronto, Toronto, Ontario, Canada
Oral presentations in the 2004 Canadian Surgery Forum, September 9-12, Ottawa, Ontario, Canada; and in the 76th Annual Meeting of the American Thyroid Association, September 29October 3, 2004, Vancouver, British Columbia, Canada.
Address correspondence and reprint requests to Dr. Julio C. Furlan, Toronto Western Hospital, 399 Bathurst Street, McL 12-407, Toronto, Ontario, Canada M5T 2S8.
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