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Original Studies |
Departments of Pediatrics (S.G., A.P., A.F., C.F., G.L.F.) and Pathology (R.C.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814; Departments of Pediatrics and Clinical Investigation, Walter Reed Army Medical Center (C.A.D.), Washington, D.C. 20307-5001; and Endocrinology Service, Memorial Sloan Kettering Cancer Center (R.M.T.), New York, New York 10021
Address all correspondence and requests for reprints to: Gary L. Francis, M.D., Ph.D., Department of Pediatrics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814. E-mail: gfrancis{at}usuhs.mil
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Abstract |
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Introduction |
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To our knowledge, none of these studies has included many children or young adults, for whom the clinical outcome of differentiated thyroid cancer is generally much better (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). If the immune response is important in suppressing the growth and recurrence of thyroid cancer, we hypothesized that children and young adults would exhibit the most intense response. To test this hypothesis, we examined a group of thyroid cancers from children and young adults and determined the presence of tumor-associated lymphocytes using routine histology and an immunohistochemical stain specific for the expression of leukocyte common antigen (LCA).
We further hypothesized that the most intense immune response would be associated with proliferation of tumor-associated lymphocytes. We tested this by staining adjacent sections for proliferating cell nuclear antigen (Ki-67). Only two previous studies have examined Ki-67 expression in thyroid carcinomas (23, 24). Neither study commented on whether Ki-67-positive cells could be lymphocytes, and neither study correlated Ki-67 expression with clinical outcome. We designed our study to determine the presence of LCA- and Ki-67-positive cells in a group of benign and malignant thyroid lesions from young patients and to correlate the number of positive cells per high power field (HPF) with clinical presentation and long-term outcome.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study received prior approval from the human use committee of the Department of Clinical Investigation, Walter Reed Army Medical Center (Washington, D.C.).
Patients
The automated centralized tumor registry of the Department of Defense was searched to identify all patients with differentiated thyroid carcinoma. Original medical records were used to construct a computerized database that includes demographic features, tumor characteristics, surgical treatment, adjunctive therapy, and clinical outcome. The extent of disease at diagnosis was classified according to the system of DeGroot et al. (25). Class 1 disease was confined to the thyroid gland, class 2 involved the regional lymph nodes, class 3 either extended beyond the capsule or was inadequately resected, and class 4 had distant metastasis. In addition, the metastasis, age, completeness of resection, invasion, and size (MACIS) and tumor node metastasis (TNM) scoring systems were used for comparison (26, 27). Recurrence was defined as the appearance of new disease (identified by radioactive iodine scan or biopsy) in any patient who had been free of disease (no disease palpable or identified by radioactive iodine scan) for a period of 4 months after initial therapy (28). Serum thyroglobulin (Tg) levels were determined in contemporary patients (normal, 3–40 ng/ml; University of Southern California Clinical Laboratories, Los Angeles, CA). The concomitant diagnosis of autoimmune thyroiditis was based on a review of the medical record, the original pathology report, and direct examination of the routine histology sections used in this study. The clinical details of some of the children and young adults in this group [137 patients with PTC and 33 with follicular thyroid carcinoma (FTC)] have been previously reported (28).
Formalin-fixed, paraffin-embedded archival tumor blocks corresponding to 39 PTC, 9 FTC, 2 medullary thyroid carcinoma (MTC), 11 benign thyroid lesions (7 benign follicular adenomas, 1 Graves’ disease, 2 multinodular goiters, and 1 autoimmune thyroiditis), and 2 normal thyroid glands were available for study. For analysis, the benign lesions were separated according to the presence of autoimmune thyroid disease and separately compared with PTC and FTC.
Immunohistochemistry
Sections from original, formalin-fixed, paraffin-embedded archival tissue blocks were sectioned and stained with hematoxylin and eosin to confirm the diagnosis and to determine the presence of tumor-associated lymphocytes by routine histology (29). The sections immediately adjacent (5 µm) were used for immunohistochemistry. Sections were deparaffinized with xylene and rehydrated through a series of graded alcohol solutions followed by nuclease-free water, and the endogenous peroxidase was quenched (3% H2O2, 30 min, room temperature). For the determination of LCA expression, antigen was retrieved using enzymatic digestion (Protease, Ventana Medical Systems, Inc., Tucson, AZ), and sections were stained on the Ventana Automated Slide Stainer (NEXES) using the Ventana diaminobenzidine detection kit (Ventana Medical Systems, Inc.). The LCA primary antibody (clone RP2/18, Ventana Medical Systems, Inc.) is a monoclonal antibody that binds the CD45RB epitope on leukocyte membranes (30). Primary antibody was then visualized using a biotin-conjugated antirabbit/mouse IgG followed by the addition of avidin/streptavidin conjugate enzyme complex and diaminobenzidine. Counterstaining was performed using Meyer’s hematoxylin and bluing reagent. A block of normal human tonsil was used as the positive control. Three separate negative controls were employed. In the first, LCA antibody was preadsorbed with specific blocking peptide (sc-1123p, Santa Cruz Biotechnology, Inc., Santa Cruz, CA). In the remaining negative controls, PBS was substituted for the primary or secondary antibodies. The number of LCA-positive cells on each of 10 HPF was determined by 2 blinded, independent examiners. The average of the 2 scores was used as the final number of LCA-positive cells per HPF.
Staining and scoring procedures for Ki-67 expression were identical, except that antigen retrieval was performed using citrate buffer (pH 6.0, 30 min), and the primary antibody was a mouse monoclonal Ki-67 antibody (catalogue no. 250-2520, Ventana Medical Systems, Inc.) (31). For the negative controls, Ki-67 antibody was preadsorbed with specific blocking peptide (sc-7844, Santa Cruz, Biotechnology, Inc.), or PBS was substituted for the primary or secondary antibodies.
Data analysis and statistical comparisons
The numbers of LCA- and Ki-67-positive cells for PTC, FTC, and benign lesions were then compared by diagnosis and, for the cancers, correlated with the histological variant, demographic features, focality of the tumor, size of the tumor, extent of disease at diagnosis (classes 1–4), and clinical outcome. For survival comparisons, PTC were stratified into 3 groups based on the presence of LCA-positive cells followed by the number of Ki-67-positive cells per HPF. Tumors without detectable LCA or Ki-67 positive cells were stratified into group 1. Tumors containing LCA-positive cells and 1–10 Ki-67-positive cells/HPF were stratified into group 2. Tumors containing LCA-positive cells and more than 10 Ki-67-positive cells/HPF were stratified into group 3.
Statistical analysis was performed using SPSS for Windows 95 (version
7.5, SPSS, Inc., Chicago, IL). The average numbers of LCA-
and Ki-67-positive cells per HPF were compared using one-way ANOVA.
Correlations were performed using Pearson correlation, and
recurrence-free survival was calculated using Kaplan-Meier survival
curves with log-rank comparison. Nonparametric analysis was performed
using either 
2 or Fisher’s exact test as
indicated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The mean
age was 16.5 ± 4.1 yr (range, 6–21 yr), mean tumor size was
2.2 ± 1.6 cm (range, 0.5–7.5 cm), and mean follow-up was
5.5 ± 4.5 yr (range, 0–20.5 yr). Twenty patients (51%) had
class 1 disease; 12 (31%) had class 2 disease; 5 (13%) had class 3
disease, and 2 (5%) had class 4 disease. The average MACIS score was
4.03 ± 0.96 (range, 3.25–7.45), and all patients except for two
(both class 4) were TNM stage 1 (26, 27). One patient,
case 5 (2.6%), had received previous radiation exposure (11 yr earlier
for treatment of Hodgkin’s lymphoma), and 7 patients (18%) had a
concomitant histological diagnosis of autoimmune thyroiditis.
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. The mean age
was 18.2 ± 2.7 yr (range, 13–21 yr), mean tumor size was
2.5 ± 1.5 cm (range, 0.2–4.5 cm), and mean follow-up was
4.8 ± 3.7 yr (range, 1.5–14 yr). The clinical characteristics of
patients with PTC and FTC are similar to those of the larger series
previously reported by our group (28).
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LCA and Ki-67 staining for a representative PTC are shown in Fig. 1. Adjacent sections were stained for
both LCA (Fig. 1, A and B) and Ki-67 (Fig. 1, C and D). LCA- and
Ki-67-positive cells were only identified in an area of
tumor-associated lymphocytes that was visible on routine histology.
This was immediately adjacent to a small area of PTC. Staining was
completely abolished by preadsorption of the antibodies or substitution
with PBS.
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; r = 0.478; P =
0.001).
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compares the numbers of LCA- and
Ki-67-positive cells per HPF for PTC, FTC, benign nonimmune, and benign
autoimmune thyroid diseases. As shown in Fig. 3A, the number of
LCA-positive cells per HPF was significantly greater in PTC compared
with FTC (32.2 ± 7.5 vs. 5.6 ± 2.5;
P = 0.002), and nonimmune benign thyroid lesions
(1.4 ± 1.2; P < 0.001). As expected, the number
of LCA-positive cells per HPF was highest in autoimmune thyroid
diseases (50.5 ± 28.6). As shown in Fig. 3B, the number of
Ki-67-positive cells per HPF was approximately 35-fold greater for PTC
(13.9 ± 4.8; P = 0.008) and 12-fold higher for
FTC (4.7 ± 2.3; P = 0.047) compared with that for
nonimmune benign lesions (0.39 ± 0.28). This study examined 2
normal thyroid glands that are included in the group of nonimmune
thyroid lesions. Neither gland contained Ki-67-positive cells; however,
one contained 10 LCA-positive cells/HPF. The other was negative for LCA
staining.
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The number of LCA-positive cells per HPF was significantly greater in multifocal compared with unifocal PTC (51.5 ± 12.5 vs. 16.4 ± 7.5, respectively; P = 0.023). Although the number of Ki-67-positive cells per HPF was approximately 3-fold greater in multifocal compared with unifocal PTC (22.7 ± 8.9 vs. 7.3 ± 5.0, respectively), the difference was not significant (P = 0.13). There were no significant correlations between the average number of LCA- or Ki-67-positive cells per HPF and patient age, tumor size, or serum TSH level. The presence or absence of serum thyroid peroxidase antibodies was well documented for only a few cases. Four PTCs were associated with positive thyroid peroxidase antibodies. The average number of LCA-positive cells per HPF for this group (38 ± 23.7) was similar to that for all remaining PTC (32.2 ± 7.5), for which the presence or absence of thyroid peroxidase antibodies is not known. Finally, there was no correlation between the length of time each tissue block had been stored and the number of LCA-positive (r = 0.006; P = 0.96) or Ki-67-positive cells (r = 0.15; P = 0.37).
Over time, six patients developed recurrent PTC (four regional lymph node and two pulmonary recurrence), and one patient developed recurrent FTC (regional lymph node). There was no difference in the number of LCA-positive cells per HPF when comparing recurrent PTC or FTC with nonrecurrent disease (PTC: recurrent, 42.1 ± 19.8; nonrecurrent, 30.7 ± 8.4; FTC: recurrent, 10; nonrecurrent, 6.6 ± 3.9). However, the number of Ki-67-positive cells per HPF was significantly less for PTC patients who developed recurrent disease (0.67 ± 0.49; range, 0–3) than for PTC patients who did not experience tumor recurrence (16.7 ± 5.7; range, 0–100; P = 0.009). The only FTC that recurred was negative for Ki-67 expression. The remaining FTC had an average of 7.3 ± 8.6 (range, 0–22) Ki-67-positive cells per HPF.
Patients with PTC were stratified into three groups based on the
presence of lymphocytes and the number of Ki-67-positive cells per HPF.
Patients in group 1 (n = 19) had PTC in which Ki-67 antigen was
not detected (0 positive cells/HPF). Patients in group 2 (n = 11)
had PTC with LCA-positive cells and a modest number of Ki-67-positive
cells per HPF (1–10 positive cells/HPF). Patients in group 3 (n =
9) had PTC with LCA-positive cells and many Ki-67-positive cells per
HPF (>10 positive cells/HPF). The clinical characteristics and outcome
for these three groups are shown in Table 3.
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, disease-free survival was
significantly improved for PTC patients with the highest number of
Ki-67-positive cells per HPF (P = 0.01, Kaplan-Meier,
log-rank comparison). The average length of follow-up for group 1 (no
Ki-67-positive cells) was approximately twice that of the other two
groups (76 ± 65 vs. 44.3 ± 32.0 and 42.3 ±
32.4 months, respectively). However, the difference was not significant
(P = 0.16), and all but one recurrence developed within
40 months (less than the average follow-up for all three groups). The
average MACIS scores, the extent of initial thyroid and lymph node
operations, the use of 131I ablation, and the
percentage of patients with concomitant autoimmune thyroiditis were
similar for all three groups.
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, recurrent disease did not develop in
any patient with PTC with more than 10 Ki-67-positive cells/HPF (group
3A). This was identical to the results shown for PTC that contained
both LCA-positive cells and more than 10 Ki-67-positive cells/HPF
(group 3). Although disease-free survival appeared to be reduced for
patients with PTC with fewer Ki-67-positive cells (groups 1A and 2A),
the difference was no longer significant (P =
0.41).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The current study determined the presence of tumor-associated lymphocytes (LCA positive) and proliferating cells (Ki-67 positive) in a group of thyroid cancers and benign lesions taken from children and young adults. The data show that the majority of PTC (65%) and FTC (75%) contain lymphocytes identified by LCA staining as well as routine histology (88%). By review of the tumor sections and original pathology reports, we identified only 7 PTC (7 of 39, 18%) and none of the FTC (0 of 9) with concomitant autoimmune thyroiditis. We believe the majority of sections demonstrating tumor-associated lymphocytes represent an immune response to the tumor itself. Using routine histology, Matsubayashi et al. (4) previously identified lymphocytes in 37.9% of adult PTC. The PTC containing lymphocytes were found to have improved disease-free survival. The percentage of childhood PTC containing lymphocytes in our study is greater than the percentage of adult PTC containing lymphocytes in the study by Matsubayashi et al. This is consistent with the hypothesis that tumor-associated lymphocytes could play an important role in the improved disease-free survival for children and young adults.
The number of LCA-positive cells per HPF was significantly greater in
PTC (
23-fold) and FTC (4-fold) than in nonimmune thyroid lesions.
As expected, the number of LCA-positive cells per HPF was greatest in
autoimmune thyroid disease. This finding directly supports previous
suggestions that thyroid cancer can by itself initiate an immune
response (5, 24). Previous studies found antithyroid
antibodies in association with approximately 50% of all thyroid
cancers (5, 32). Unfortunately, our retrospective database
did not have complete documentation of thyroid peroxidase antibody
testing in all patients (28). Nevertheless, we found a
similar number of LCA-positive cells in PTC from patients with positive
antibodies compared to all of the remaining PTC regardless of antibody
status.
By comparing routine histology and LCA and Ki-67 staining for corresponding regions on adjacent tissue sections, we were able to show in almost all cases that Ki-67-positive cells could be identified only in regions that contain lymphocytes (identified by routine histology and LCA staining). There were four exceptions, three of which were FTC. None of the four developed recurrent disease, thus limiting our ability to speculate on the impact of these proliferating nonlymphocytic cells on disease-free survival. Only two previous studies have examined Ki-67 expression in thyroid cancers (23, 24). Both found Ki-67 expression in only a small percentage of cells in PTC or FTC. Rigaud et al. identified Ki-67 expression in 2–5% of all the cells in FTC, but were unable to correlate the number of Ki-67-positive cells with clinical outcome (23). We believe it is possible that the LCA-negative, Ki-67-positive cells that we identified in these three FTC could represent dividing thyroid follicular cells. If so, the number of Ki-67-positive cells is consistent with the low number found by Rigaud et al.
The relationship between Ki-67-positive lymphocytes and clinical outcome is the most important observation of our study. Over time, six patients developed recurrent PTC (four in the regional lymph nodes and two pulmonary recurrence), and one patient developed recurrent FTC (regional lymph nodes). The extent of initial thyroid surgery, lymph node dissection, and use of adjunctive radioactive iodine ablation were similar for patients with recurrent disease and patients who did not develop recurrent disease. The number of LCA-positive cells per HPF was similar for recurrent and nonrecurrent PTC as well as FTC. However, the number of Ki-67-positive cells per HPF was 25-fold less for PTC patients who developed recurrent disease (0.67 ± 0.49; range, 0–3) compared with PTC patients without recurrence (16.7 ± 5.7; range, 0–100; P = 0.009). When patients with PTC were stratified according to the presence of lymphocytes and the intensity of Ki-67 expression, those with the highest number of Ki-67-positive lymphocytes per HPF had significantly improved disease-free survival (P = 0.01). This difference is even more meaningful, because the group with the highest number of Ki-67-positive cells per HPF (group 3) also had the highest percentage of multifocal tumors (67%; group 1, 36%; group 2, 50%). We have previously shown that multifocal PTC are more likely to recur in children and young adults (28). This should have made the recurrence risk greater, not lesser, for the PTC with the highest number of Ki-67-positive cells per HPF. The number of cases associated with Hashimoto’s thyroiditis tended to be greater for group 3, but the difference was not statistically significant [2 of 19 (10%) in group 1; 2 of 11 (18%) in group 2, and 3 of 9 (33%) in group 3].
Disease-free survival was also analyzed according to the number of Ki-67-positive cells per HPF without regard to the presence or absence of lymphocytes. Exactly as shown for patients with PTC that contained lymphocytes and more than 10 Ki-67-positive cells/HPF, none of the patients with PTC that contained more than 10 Ki-67-positive cells/HPF (group 3A) developed recurrent disease. Although disease-free survival appeared to be reduced for patients with PTC with fewer Ki-67-positive cells per HPF, the difference was no longer significant (P = 0.41). The loss of significance could be due to the fact that patients with PTC with a modest number of Ki-67-positive cells per HPF (group 2A, 1–10/HPF) had a slightly higher recurrence risk than did those with PTC containing no Ki-67-positive cells per HPF (group 1A).
There was no significant correlation between the number of LCA-positive cells per HPF and the extent of disease at diagnosis. However, the number of Ki-67-positive cells per HPF was 4.5-fold greater in PTC with regional lymph node metastasis (class 2, 30.5 ± 12.3) compared with PTC confined to the thyroid gland (class 1, 6.8 ± 5.0; P = 0.047). The numbers of Ki-67-positive cells per HPF for invasive PTC (class 3, 10.8 ± 9.8) and for PTC with distant metastasis (class 4, 0 positive cells/HPF for both tumors) were similar to the number found in class 1 tumors. We also correlated the number of Ki-67-positive cells per HPF with other staging systems. TNM staging was of limited value in the assessment of our patients, who were all less than 45 yr of age. In these young patients, all tumor and node classes are condensed into stage 1 unless distant metastases are present (stage 2) (27). In our study there were only two subjects at TNM stage 2, which limited the ability of TNM classification to discriminate outcome variables. The MACIS system includes patient age, but also tumor size, local invasion, metastasis, and inadequate resection as risk variables (26). There was no significant correlation between the number of Ki-67-positive cells per HPF and the MACIS score (r = 0.03; P = 0.86). In addition, the average MACIS scores were similar for all three groups of PTC stratified according to the presence of lymphocytes and the number of Ki-67-positive cells per HPF (group 1, 4.13 ± 0.26; group 2, 3.87 ± 0.19; group 3, 3.81 ± 0.22). These data suggest that the number of proliferating, tumor-associated lymphocytes appears to be important in predicting recurrence for young patients, but is not addressed by the MACIS score (predominantly determined by the extent of disease at diagnosis). In support of this idea, the average MACIS score for patients with recurrent disease (4.60 ± 0.59) did not differ from that for patients without recurrence (3.96 ± 0.14; P = 0.13), and both fell within the lowest MACIS risk group (MACIS score <6.0) (26). In addition, multivariate analysis has previously shown multifocal disease (which is not addressed by the MACIS score) to be the major predictor for recurrence of PTC in children and young adults (28).
Of note, PTC with distant metastasis (class 4, n = 2) had the lowest number of LCA- and Ki-67-positive cells per HPF. Although the number of cases is too small to attach statistical validity, this observation is consistent with the hypothesis that the absence of proliferating lymphocytes in these lesions could favor metastasis. In a previous study limited to adults, Matsubayashi et al. (4) also showed that the extent of disease at diagnosis was lower for PTC that contain lymphocytes.
We found a significantly greater number of LCA-positive cells per HPF in multifocal compared with unifocal PTC (multifocal, 51.5 ± 12.5; unifocal, 16.4 ± 7.5; P = 0.023). Although the number of Ki-67-positive cells per HPF was approximately 3-fold greater in multifocal PTC compared with unifocal PTC, the difference was not significant. The previous study by Matsubayahi et al. also found a greater percentage of multifocal disease among the PTC that contained lymphocytes (44.4%) compared with PTC without lymphocytes (25.4%) (4).
Our study included too few MTC to derive significant observations; however, Ki-67 was undetectable in either of the two MTC. In a previous study, Rigaud et al. (23), examined two MTC, one of which was negative for Ki-67. Another study by Wallin et al. (24) included five MTC, all of which were positive for Ki-67. The differences in these findings are not clear, but could relate to the very small number of MTC in all three studies.
Our findings are limited by the retrospective nature of the clinical data (28). The majority of patients received their care before the routine use of serum Tg measurements for the detection of recurrent or persistent disease. For this reason we are unable to correlate Ki-67-stratified outcome with serum Tg values for all of the patients in our study. As previously reported, we defined recurrence for this study as the appearance of new disease (identified by radioactive iodine scan or biopsy) in any patient who had been free of disease (no disease palpable or identified by radioactive iodine scan) for a period of 4 months after initial therapy (28). Although some of these historical patients might have had detectable serum Tg and would therefore have been incorrectly identified as free of disease, the treatment of such 131I scan-negative, Tg-positive patients is controversial (33). Furthermore, in all of our contemporary patients classified as free of disease, serum Tg values were less than 2 ng/mL (normal, 3–40 ng/mL), and they were undetectable in 71% of disease-free patients.
In conclusion, the current study has shown that the majority of thyroid cancers from children and young adults contain tumor-associated lymphocytes. Thyroid cancers that contain proliferating, tumor-associated lymphocytes have a significantly reduced risk for recurrence. This could be an important factor in the improved disease-free survival for this age group. Additional study is required to validate these observations in patients representing a wider age range and for whom serum Tg measurements are available.
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Acknowledgments |
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Footnotes |
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Received September 20, 2000.
Revised November 3, 2000.
Accepted November 20, 2000.
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References |
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