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*Substance via MeSH
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*Thyroid Cancer
The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 9 4418-4425
Copyright © 2003 by The Endocrine Society

Papillary Thyroid Carcinomas from Young Adults and Children Contain a Mixture of Lymphocytes

Jitu Modi, Aneeta Patel, Richard Terrell, R. Michael Tuttle and Gary L. Francis

Department of Pediatrics (J.M., A.P., R.T., G.L.F.), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814; Department of Endocrinology (R.M.T.), Memorial Sloan Kettering Cancer Center, New York, New York 10021; and Departments of Pediatrics and Clinical Investigation (G.L.F.), Walter Reed Army Medical Center, Washington, DC 20307-5001

Address all correspondence and requests for reprints to: Gary L. Francis, M.D., Ph.D., Professor, Department of Pediatrics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814. E-mail: gfrancis{at}usuhs.mil.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The immune response appears to be important in preventing metastasis and recurrence of thyroid cancer. We previously showed that papillary thyroid carcinoma (PTC) from children and adolescents that contain the most numerous proliferating lymphocytes have the best prognosis. However, the types of lymphocytes involved are not yet known. To further define this, we examined 21 PTCs from patients 21 yr of age or younger (52% were 18–21 yr of age) for the presence of CD4+ (helper), CD8+ (killer), CD19+ (B cells), and CD56+ (natural killer) cells as well as proliferating lymphocytes (Ki-67+). Nearly half the PTCs contained CD4+ (9 of 21, 43%), CD8+ (8 of 21, 38%), or CD19+ (10 of 21, 48%) lymphocytes. Only one PTC (1 of 21, 5%) contained CD56+ lymphocytes, and none contained all four cell types. By dual staining, none of these lymphocytes were proliferating (Ki-67+). However, PTCs containing either CD8+ cells (n = 8) or a combination of CD4+, CD8+, and CD19+ cells (n = 5) contained more numerous proliferating lymphocytes than did PTCs containing any other combination (14.2-fold increase, P = 0.03 and 13.1-fold increase, P = 0.003, respectively). During follow-up, none of the PTCs containing either CD8+ lymphocytes or the combination of CD4+, CD8+, and CD19+ lymphocytes recurred. However, the cohort is too small and the follow-up inadequate to provide accurate information on the clinical impact of these immunological findings. We conclude that the immune response against PTC is important and also complex, involving more than one type of lymphocyte.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE IMMUNE RESPONSE appears to be important in preventing metastasis and recurrence of thyroid cancer (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14). This is based on several observations. First, patients with autoimmune thyroiditis and papillary thyroid carcinoma (PTC) generally have improved disease-free survival (15, 16). Second, lymphocytic infiltration of adult PTC(s) is associated with lower-stage disease at diagnosis and reduced recurrence risk (17). Third, most studies have shown that children and adolescents with PTC have a more favorable prognosis than adults (18, 19). We previously showed that PTCs from children and adolescents contain more numerous lymphocytes than PTCs from adults, and that PTCs with the most numerous proliferating lymphocytes have the best prognosis (6). In addition, we showed that PTCs from children and adolescents express the B7-1 and B7-2 coactivators (20). The B7-2 coactivator binds to the CTLA-4 receptor on T cells in which it suppresses T-cell growth (21). Consistent with this effect, PTCs with intense B7-2 expression had the greatest risk of recurrence (20).

Taken together, these observations emphasize the importance of lymphocytic infiltration and proliferation in preventing thyroid cancer recurrence. However, the type(s) of lymphocytes involved in this response, the factors that attract lymphocytes and induce their proliferation, and the mechanism(s) by which proliferating lymphocytes affect thyroid cancer remain unknown.

Tumor-associated lymphocytes could be T cells and important in cell-mediated tumor destruction. They could also be B cells and important in antibody-mediated tumor destruction, or natural killer (NK) cells and important in direct cytotoxic tumor destruction. The type(s) of lymphocytes could determine the nature of the immune response against PTC. Thyroid cells, like all nucleated cells, can present antigen to lymphocytes (22, 23, 24, 25). Thyroid cells constitutively express the major histocompatibility complex (MHC)-I that presents antigens that are recognized only by CD8+ lymphocytes (23). Once activated, CD8+ cells are directly cytotoxic. The MHC-II complex can be up-regulated in thyroid cells by interferon-{gamma} (IFN{gamma}) or TNF{alpha} (23). Antigens presented by the MHC-II complex can be recognized only by CD4+ lymphocytes. A subset of these CD4+ T cells produce Th-1 cytokines (IFN{gamma} and IL-2) that are important in stimulating macrophages and cell-mediated immunity, and another subset produces Th-2 cytokines (IL-4 and IL-5) that stimulate B cells and antibody production (23). CD4+ cells are not directly cytotoxic, but they initiate an immune response that involves either the cell-mediated or serum-mediated pathways. A final effector cell type of the immune response is the NK cell. NK cells (CD56+) can react directly with IL-2 or IL-12, causing activation and production of IFN{gamma} (23). Among the subsets of T cells then, CD4 and CD8 distinguish cytotoxic killer cells (CD8+) from helper cells (CD4+), and CD19 is expressed by antibody-producing B cells, and CD56 is expressed by NK cells.

We hypothesized that the immune response against thyroid cancers would involve both cellular and humoral components of the immune system and tested this by determining the types of lymphocytes (CD4+, CD8+, CD19+, and CD56+) present in PTC from children and young adults. We found that PTC containing either CD8+ lymphocytes or a combination of CD4+, CD8+, and CD19+ lymphocytes also contained the most numerous proliferating lymphocytes and did not develop clinical signs of recurrence, suggesting that the immune response against PTC is not only important but also complex.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Approval

This study received prior approval and funding (WU# 02-65006) from the Human Use Committee of the Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, DC.

Patients The automated centralized tumor registry of the Department of Defense (ACTUR) was searched to identify all patients diagnosed with PTC before the age of 22 yr. Original medical records were used to construct a computerized database that includes demographic features, tumor characteristics, surgical treatment, adjunctive therapy, and clinical outcome (19). The extent of disease at diagnosis was classified according to the system of DeGroot et al. (26). 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/size (MACIS) scoring system was also used for comparisons (27). As in our previous studies, 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 following initial therapy (14, 19, 28, 29, 30, 31, 32, 33). This definition has been useful for comparison of our historical data that span several decades and include many patients that were eventually lost from follow-up. However, this definition is no longer consistent with the contemporary definition of freedom from disease, which is based on undetectable suppressed serum thyroglobulin (Tg) levels and stimulated Tg levels less than 2 ng/ml (34, 35, 36, 37). The majority of patients in our study received their medical care before the routine use of serum Tg levels. For this reason, Tg levels are not used in our definitions; however, Tg levels were determined for 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.

Sufficient formalin-fixed, paraffin-embedded archival tumor tissue was available to stain 21 PTCs for the presence of CD4+, CD8+, CD19+, and CD56+ lymphocytes by specific immunohistochemical staining. The clinical details of some of these patients have been previously published by our group (19).

Immunohistochemistry

Sections from original, formalin-fixed, paraffin-embedded archival tissue blocks were sectioned and stained with hematoxylin and eosin to confirm the diagnosis and determine the presence of tumor-associated lymphocytes by routine histology (6). 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. Antigen retrieval was performed according to the manufacturer’s suggestions using TRILOGY (Cell Marque, Hot Springs, AR), and endogenous peroxidase was quenched (3% H2O2, 30 min, room temperature). Sections were incubated with primary anti-CD4 (Novacastra, Newcastle upon Tyne, UK), anti-CD8 (Caltag Laboratories, Burlingame, CA), anti-CD19 (Cell Marque, UK) or anti-CD56 (Cell Marque, UK) and secondary biotinylated anti-IgG. Sections were stained on the Ventana automated slide stainer (NEXES, Tucson, AZ) using the Ventana diamino-benzidine (DAB) detection and amplification kits (Ventana Medical Systems, Tucson, AZ), followed by enhanced DAB with nickel chloride and hematoxylin counterstain. The presence of CD4+, CD8+, CD19+, and CD56+ lymphocytes was then determined on each of 10 high-power fields by two blinded, independent examiners. The interobserver concordance was greater than 95%.

Dual staining for Ki-67 and either CD4 or CD19 was initiated as outlined above, after which slides were incubated with anti-Ki-67 (2 h, room temperature, Beckman Coulter, Inc., Fullerton, CA) using the Ventana enhanced alkaline phosphatase red detection kit. Dual staining for either CD8 or CD56 was performed in the reverse sequence with anti-Ki-67 (2 h, room temperature, Beckman Coulter, Inc.) and the Ventana DAB detection and amplification kits, followed by anti-CD8 or anti-CD56 and the Ventana enhanced alkaline phosphatase red detection kit. The presence of dual-stained lymphocytes was determined by two blinded, independent examiners with greater than 90% concordance.

Normal human tonsil was used as the positive control. Separate negative controls were performed for each CD marker in which PBS was substituted for the primary or secondary antibodies.

In a previous publication, we determined the intensity of vascular endothelial growth factor (VEGF) expression by several of these PTCs (38). In that study, we showed that PTC with the most intense expression of VEGF had an increased risk of recurrence. The data from that study were used to correlate the presence of each lymphocyte marker with the intensity of VEGF expression.

Data analysis and statistical comparisons

The presence of CD4+, CD8+, CD19+, and CD56+ cells was correlated with the histologic variant, demographic features, focality of the tumor, size of the tumor, extent of disease at diagnosis, and clinical outcome. Statistical analyses were performed using SPSS for Windows 95 (version 7.5, SPSS Inc., Chicago, IL). The average number of positive cells per high power field was 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 the {chi}2 or Fisher’s exact test as indicated.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The clinical features of the 21 patients with PTC are shown in Table 1Go. They ranged in age from 6–21 yr (mean 17 ± 4 yr) and had PTC with an average size of 2.1 ± 1.7 cm (range 0.5–7.5 cm). Eleven patients (52%) had class 1 disease; eight (38%) had class 2 disease; one (5%) had class 3 disease; and one (5%) had class 4 disease. The average MACIS score was 3.92 ± 0.75 (range 3.25–6.25). One patient had received previous radiation therapy for lymphoma and one patient had a concomitant diagnosis of autoimmune thyroiditis. The patients were followed up for an average of 55 ± 38 months (range 0–118 months, median 50 months). During that time, three developed clinical signs of recurrent disease (12, 17, and 67 months, respectively). The clinical details, treatment, and outcome for all 21 patients are similar to those of a larger cohort previously published by our group (19), suggesting the findings are representative of PTC from children and young adults.


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  		TABLE 1. Clinical features and lymphocyte staining for PTC

 
Representative staining for CD4, CD8, CD19, and CD56 is shown in Fig. 1Go. Almost half of the PTCs contained CD4+ cells (Fig. 1AGo, 9 of 21, 43%), CD8+ cells (Fig. 1BGo, 8 of 21, 38%), or CD19+ cells (Fig. 1CGo, 10 of 21, 48%). These were frequently detected in the periphery of the lesion. Only a small minority (Fig. 1DGo, 1 of 21, 5%) contained CD56+ cells.



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  		FIG. 1. Representative staining for CD4+, CD8+, CD19+, and CD56+ lymphocytes. Sections were independently stained for each lymphocyte marker. Numerous CD4+ lymphocytes (A), CD8+ lymphocytes (B), CD19+ lymphocytes (C), and a few CD 56+ lymphocytes (D) were found in these PTCs. Sections were sequentially stained for proliferating cell nuclear antigen (Ki-67) and each of the lymphocyte markers. Although Ki-67+ lymphocytes were abundant (E–H), no cells could be identified that stained with Ki-67 and any of the lymphocyte markers: CD4 (E), CD8 (F), CD19 (G), or CD56 (H).

 
A dual-staining technique was also used to sequentially stain the same sections for both Ki-67 (proliferating cell nuclear antigen) and each of the CD markers. Ki-67+ lymphocytes were found in almost half the sections (10 of 21, 48%) and were also more commonly seen in the periphery of the lesions. However, none of the sections revealed CD4+, CD8+, CD19+, or CD56+ cells that were also positive for the proliferating nuclear antigen, Ki-67 (Fig. 1Go, E–H).

PTCs were also stratified according to the presence or absence of CD4+ lymphocytes (Table 2Go). Patient age, tumor size, MACIS score, and the length of follow-up were similar for PTC that either did or did not contain CD4+ cells. Although the number of lymphocytes and proliferating lymphocytes/high-power field was greater in the PTCs that contained CD4+ cells, compared with PTCs that did not contain CD4+ cells (2.4-fold and 10-fold, respectively), neither difference achieved statistical significance (P = 0.15 and 0.11, respectively). During follow-up, three patients developed signs of clinical recurrence: one contained CD4+ cells and the other two did not. Serum Tg values were not available to ascertain biochemical recurrence.


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  		TABLE 2. Comparison of PTC stratified according to CD4(+) lymphocytes

 
PTCs were then stratified according to the presence or absence of CD8+ lymphocytes. As shown in Table 3Go, patient age, tumor size, MACIS score, and the length of follow-up were similar for PTCs that either did or did not contain CD8+ cells. However, the number of lymphocytes and proliferating lymphocytes/high-power field was greater in the group of tumors containing CD8+ cells, compared with PTCs that did not contain CD8+ cells (2.8-fold increase, P = 0.04 and 14.2-fold increase, P = 0.03, respectively). During follow-up, three PTCs developed clinical signs of recurrence, none of which contained any CD8+ cells. Serum Tg values were not available to ascertain biochemical recurrence.


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  		TABLE 3. Comparison of PTC stratified according to CD8(+) lymphocytes

 
When stratified according to the presence or absence of CD19+ lymphocytes (Table 4Go), patient age, tumor size, MACIS score, and the length of follow-up were similar for PTCs that either did or did not contain CD19+ cells. However, the number of lymphocytes and proliferating lymphocytes/high-power field was greater (3.8-fold and 49.2-fold, respectively) in the PTCs that contained CD19+ cells, compared with PTCs that did not contain CD19+ cells. The difference was significant (P = 0.035) when comparing the number of lymphocytes/high-power field but approached significance (P = 0.076) only when comparing the number of proliferating lymphocytes/high-power field. During follow-up, three patients developed clinically evident recurrence: One contained CD19+ cells and the other two did not. Serum Tg values were not available to ascertain biochemical recurrence.


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  		TABLE 4. Comparison of PTC stratified according to CD19(+) lymphocytes

 
Only one PTC contained CD56+ lymphocytes, precluding statistical analyses. That particular case had similar patient age (15 yr), tumor size (2.4 cm), and MACIS score (3.82) when compared with other PTCs in our study. However, the tumor contained very few lymphocytes (one cell) or proliferating lymphocytes (one cell) /high-power field. During follow-up, none of the clinically recurrent PTCs (n = 3) contained CD56+ cells.

None of the tumors contained all four subtypes of lymphocytes; however, five PTCs (24%) contained CD4+, CD8+, and CD19+ lymphocytes (Table 5Go). All were class 1 (confined to the gland) or class 2 (spread to regional nodes but not beyond), and none recurred. These five tumors contained significantly more numerous proliferating lymphocytes/high-power field (44.6 ± 22.9, n = 5) when compared with tumors that contained any other combination of lymphocyte subtypes (3.4 ± 2.1, P = 0.003, n = 16). During follow-up, three PTCs developed clinical recurrence, none of which contained CD4+, CD8+, and CD19+ lymphocytes. However, the difference in recurrence rate was not significant (P = 0.55), and serum Tg values were not available to ascertain whether additional patients had biochemical evidence of recurrence.


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  		TABLE 5. Comparison of PTC stratified according to CD4(+), CD8(+), and CD19(+) lymphocytes

 
Among the PTCs used in this study, 17 had been previously examined by immunostaining to determine the intensity of VEGF expression (38). The presence of each CD marker (CD4+, CD8+, and CD19+) was correlated with the intensity of VEGF expression. As shown in Tables 2–5GoGoGoGo, average VEGF expression was more intense among PTCs that contained CD19+ or the combination of CD4+, CD8+, and CD19+ lymphocytes (P = 0.011 and 0.036, respectively). In addition, there was a suggestion that the average VEGF expression might also be greater in PTCs that contained CD8+ lymphocytes, but the difference approached only statistical significance (P = 0.068). There was no difference in VEGF expression between PTCs that did or did not contain CD4+ lymphocytes.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Tumor-infiltrating lymphocytes have been associated with less extensive disease at diagnosis and improved disease-free survival for adults with PTC (17). In addition, PTCs from children and adolescents have the most favorable prognosis, especially when numerous tumor-associated, proliferating lymphocytes are present (6). These data suggest the immune response could be important in preventing metastasis and recurrence of thyroid cancer. Alternatively, lymphocytic infiltration might induce symptoms that would prompt earlier intervention, leading to an improved outcome. In either event, these data underscore the importance of the immune response, but the type(s) of lymphocytes involved are not yet known.

In the current study, we found that PTCs from children and young adults frequently contain CD4+ (43%), CD8+ (38%), or CD19+ (48%) lymphocytes and that several (24%) contain all three types. Only a small minority (5%) contain CD56+ lymphocytes. This finding supports our previous observations that PTCs from children and adolescents contain numerous lymphocytes (6). In addition, the data suggest that an array of different cell types could be involved in this immune response.

We previously showed that PTCs from children and adolescents that contain the most numerous proliferating lymphocytes have the most favorable prognosis (6). In the present study, we were unable to identify any subset of lymphocytes that is actually proliferating in these tumors. We found no cells that stained for both Ki-67 (a proliferating cell nuclear antigen) and any of the lymphocyte markers (CD4, CD8, CD19, or CD56). We did find, however, that PTCs containing either CD8+ lymphocytes or the combination of CD4+, CD8+, and CD19+ lymphocytes also contained more numerous proliferating lymphocytes. We believe these data support the concept that the immune response against PTCs is broad and could involve clonal expansion of a reactive lymphocyte population (Ki-67+) along with either recruitment or generation of lymphocytes that effect cell-mediated (CD4+ and CD8+) and antibody-mediated (CD19+) immunity.

To our knowledge, no previous study has examined these questions in PTC. However, a recent study by Zhang et al. (39) found that 54.8% of epithelial ovarian cancers were infiltrated by T cells. Patients whose tumors contained T cells were more likely to respond to therapy and survive beyond 5 yr (38% vs. 4.5%). In addition, the presence of T cells correlated with higher levels of IFN{gamma}, IL-2, and chemokines. In contrast, VEGF expression was increased in tumors that lacked T-cell infiltration.

We had previously examined 17 of the PTCs in our study for the expression of VEGF (6). By correlating the intensity of VEGF expression with each of the lymphocyte markers, we were able to show that PTCs containing either CD19+ lymphocytes or all three markers (CD4+, CD8+, and CD19+) had more intense VEGF expression than PTCs containing other combinations of lymphocyte subsets. Although the number of tumors in these two groups was small (10 PTCs contained either CD19+ or CD4+, CD8+, and CD19+ lymphocytes), the average tumor size also tended to be greater (2.5 ± 0.7 vs. 1.8 ± 0.3 cm, P = 0.36), consistent with increased VEGF expression (38). This relationship suggests that a broad-based immune response might be able to prevent recurrence despite other unfavorable prognostic indicators such as larger size and increased VEGF expression.

Two different hypotheses could explain such a potential relationship between tumor-infiltrating lymphocytes and VEGF expression. First, it is possible that cytokines, produced by tissue-infiltrating lymphocytes, could increase VEGF expression. In direct support of this hypothesis, cytokines such as IL-3 and TNF{alpha} have been shown to up-regulate VEGF transcription (40, 41). An alternative hypothesis suggests that increased VEGF expression might facilitate migration of lymphocytes into thyroid cancers. VEGF has been shown to increase vascular permeability (42), plasma extravasation (43), and neutrophil transendothelial migration (44), all of which might facilitate lymphocyte ingress.

When our analysis was limited to PTCs containing all three types of lymphocytes (CD4+, CD8+, and CD19+, n = 5) the majority of PTCs (3 of 5, 60%) were multifocal. Previous studies have shown that multifocal disease is also a risk factor for recurrence (19, 38). Despite this fact, none of the PTCs that contained all three types of lymphocytes (CD4+, CD8+, and CD19+) extended beyond the capsule (class 3), had distant metastases (class 4), or developed clinical recurrence. Furthermore, all five patients were alive with no evidence of disease at last follow-up. The number of recurrent PTCs in our study was too small (n = 3), and the Tg data inadequate to provide sufficient power or more accurate information to further interpret these findings.

We should emphasize that our findings are limited by several factors. First, the number of patients was small and more than half the patients were between 18 and 21 yr of age. Second, the clinical data were derived from a retrospective database that does not represent a prospective, randomized comparison of treatments and outcomes (19). Third, 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 were unable to correlate serum Tg values with the presence or absence of any lymphocyte subset. Most importantly, current studies indicate that stimulated serum Tg values greater than 2 ng/ml indicate a high probability of persistent disease (34, 35, 37). None of our historical patients had serum Tg values available for analysis, and it is likely that some of these patients would have had stimulated serum Tg values greater than 2 ng/ml and would therefore have been incorrectly identified as free of disease. For this reason, we were unable to provide accurate information about the long-term clinical impact of our immunological findings.

In conclusion, the current study has shown that the majority of PTCs from children and young adults contain CD4+, CD8+, or CD19+ tumor-associated lymphocytes. None of these subsets appear to be proliferating, but the PTCs that contain CD8+ lymphocytes and especially those that contain all three (CD4+, CD8+, and CD19+) types of lymphocytes also contain an increased number of proliferating lymphocytes. These observations suggest that the immune response against PTCs is not only important but is also complex and involves more than one arm of the immune system.


   Footnotes
 
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or to reflect the opinions of the Uniformed Services University of the Health Sciences, the United States Army, or the Department of Defense.

Abbreviations: DAB, Diamino-benzidine; IFN{gamma}, interferon-{gamma}; MACIS, metastasis/age/completeness of resection/invasion/size scoring system; MHC, major histocompatibility complex; NK, natural killer; PTC, papillary thyroid carcinoma; Tg, thyroglobulin; VEGF, vascular endothelial growth factor.

Received February 27, 2003.

Accepted May 15, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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B Jarzab, D Handkiewicz-Junak, and J Wloch
Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review
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