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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 8 3975-3980
Copyright © 2001 by The Endocrine Society

Other Original Articles

nm23-H1 Immunoreactivity as a Prognostic Factor in Differentiated Thyroid Carcinoma

Carles Zafon, Gabriel Obiols, Josep CastellvÍ, Natalia Tallada, Pere Galofré, Enrique Gemar, Jordi Mesa and Rafael Simó

Division of Endocrinology (C.Z., G.O., J.M., R.S.), Department of Pathology (J.C., N.T.), Department of Nuclear Medicine (P.G.), and Unit of Endocrinological Surgery (E.G.), Hospital General i Universitari Vall d’Hebron, Barcelona 08035, Spain

Address all correspondence and requests for reprints to: Rafael Simó, M.D., Division of Endocrinology, Hospital General Vall d’Hebron, Pg. Vall d’Hebron 119–129, 08035 Barcelona, Spain. E-mail: rsimo{at}hg vhebron.es.

Abstract

Several prognostic factors have been proposed to identify the patients at risk to develop metastases in differentiated thyroid carcinoma. Reduced nm23-H1 expression (a metastatic suppressor gene) has been correlated with high tumor metastatic potential in various human carcinomas, but the results obtained in differentiated thyroid carcinoma remain controversial.

To elucidate the usefulness of nm23-H1 as a differentiated thyroid carcinoma prognosis factor, we evaluate the relationship between nm23-H1 immunoreactivity as well as both clinical status and patient outcome. For this purpose, thyroid resected specimens obtained from 94 differentiated thyroid carcinoma consecutive patients (64 papillary and 30 follicular) with at least 5 yr of follow-up were stained using monoclonal antibody to nm23-H1.

We did not observe any relationship between nm23-H1 immunoreactivity and age, gender, initial differentiated thyroid carcinoma stage, local recurrence, or distant metastases in patients with papillary carcinoma. However, in patients with follicular carcinoma, a significant inverse association between metastatic disease and the expression of nm23-H1 product was obtained (P < 0.05). In addition, significant differences were found in the survival curves according to nm23-H1 immunoreactivity (log-rank P < 0.01). Finally, nm-23-H1 immunoreactivity was more specific but less sensitive than AMES score to predict metastases.

In conclusion, our results suggest that nm23-H1 immunostaining could be added to the classic prognostic factors currently used to predict the outcome of patients with follicular thyroid carcinoma.

DIFFERENTIATED THYROID CARCINOMA (DTC) is a relatively uncommon tumor, accounting for less than 1.5% of all cancers (1, 2). Most papillary and follicular carcinomas have an excellent prognosis, but when metastases appear the mortality rate rises dramatically. Several prognostic factors have been proposed to identify patients at risk to develop metastases (3, 4, 5, 6, 7, 8). However, there are still some patients without any of these adverse prognostic indicators, who subsequently develop disseminated disease. The role of molecular genetics to identify this subgroup of patients is unquestionable (9, 10, 11). Over recent years, it has been demonstrated that metastasis-suppressor genes (MSG) are crucial in the control of the metastatic potential of several carcinomas (12). nm23 is a MSG, and until now six different human genes (H1-H6) have been reported (13, 14, 15, 16, 17, 18), but only H1 and H2 have been tested for their role in tumor spread. nm23 was first identified by Steeg and co-workers in 1988 (13) from variant lines of murine melanoma. These authors found an inverse correlation between nm23 gene expression and the metastatic potential. This protective control on metastatic behavior was later confirmed in human neoplasms, initially in breast carcinoma (19, 20) and after in melanoma (21, 22), hepatocellular carcinoma (23, 24), and ovarian carcinoma (25, 26). However, in hematological neoplasms (27, 28) and prostatic carcinoma (29), the higher expression of nm23 has been associated with worse prognosis. In addition, in other types of cancer (i.e. colorectal, lung, gastric, and renal cell carcinoma), the role of nm23 is less conclusive (30, 31, 32, 33, 34, 35, 36).Therefore, it seems that the biological significance of nm23 gene expression depends on the type of neoplasic tissue.

There are a few studies of nm23 in patients with DTC, and the results are conflicting (37, 38, 39, 40, 41, 42, 43, 44). These controversial results could be partly attributed to methodological aspects such as the number and selection of the patients as well as the specimens selected for the analysis. In the present study, we have investigated the expression of nm23-H1 product in the neoplasic thyroid tissue obtained from a substantial number of patients with DTC with a follow-up longer than 5 yr, and provide evidence that nm23-H1 protein immunoreactivity is inversely associated with metastatic potential for follicular but not for papillary thyroid carcinoma.

Materials and Methods

Therapeutic protocol and baseline characteristics of patients

Thyroid resected specimens obtained from 94 consecutive patients diagnosed with DTC attending the Thyroid Carcinoma Unit of a university hospital from 1978–1994 were used for the study. Therefore, all patients have at least 5 yr of follow-up. Initial surgical procedure was total or near-total thyroidectomy in all cases followed by L-T4 treatment to suppress TSH levels. Within 3 months after surgery, all patients were submitted to 131I whole body scan (WBS) in hypothyroid state (TSH > 30µU/ml), and treated with 131INa (100–300 mCi) for ablation of postsurgical thyroid residual tissue. After postoperative ablation, the patients were rescanned within 1 yr, in hypothyroid state, and serum thyroglobulin (Tg) was measured. The patients were considered "cured" if they accomplished the following requirements: 1) free of signs and symptoms related to the disease; and 2) negative WBS and indetectable serum Tg after withdrawal of T4- suppressive therapy.

During follow-up, all patients received treatment with suppressive doses of L-T4. WBS and serum Tg determination were performed in the follow-up studies (yearly for the first 5 yr and every 2 yr thereafter) after withdrawal of T4-suppresive therapy for 4 wk and the observance of a low-iodine diet for at least 1 wk before the scintigraphic procedure. The activity of 131INa administrated for WBS was 5 mCi (182 megabecquerels). This dose did not change during the study. The cut-off value to be considered "positive" for thyroglobulin was 5 ng/ml until 1994. Since then, the method has been changed (immuno-radiometric assay, Biocode, Liege, Belgium), and the cut-off lowered to 2 ng/ml.

Recurrence was classified as local recurrence or distant metastases. Chest and bone x-ray, neck ultrasonography, magnetic resonance imaging, and computed tomography were additional procedures used when necessary. The main baseline clinical characteristics of the patients according to histological type are shown in Table 1Go.


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  		Table 1. Clinical characteristics of patients included in the study

 
Evaluation of patient’s outcome

The patients outcome according to the hystologic type of DTC is shown in Table 2Go.


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  		Table 2. Outcome of patients with differentiated thyroid carcinoma

 
Papillary carcinomas. A total of 64 patients with papillary carcinoma were followed for a mean of 12.3 ± SD, 4.5 yr (median 12 yr [range 4–21]). Nine of these patients (14%) had local recurrence in the thyroid bed (mean time, 5.1 ± SD, 3.2 yr after the initial treatment (median 4 yr [range 2–10]), and in 6 other patients (9.3%) distant metastases were discovered. In 3 of the latter patients, metastatic disease was detected at diagnosis, whereas in the other three the metastatic lesions were found during follow-up (mean, 7.6 ± SD, 3.2 yr; median 9 yr [range 4–10]). The metastatic involvement is displayed in Table 2Go. Two patients died (3.1%) 8 and 12 yr after initial therapy, and in both cases the death was due to thyroid cancer.

Follicular carcinomas. The median follow-up for the 30 follicular carcinomas was 12.8 ± SD, 6.4 yr (median 14.5 yr [range 2–21]). Seven patients (23.3%) developed local recurrence (mean, 3.8 ± SD, 1.5 yr; median 4 yr [range2–6]). Six patients (20%) had metastatic carcinoma on the initial treatment and 5 (16.6%) during the course of their disease (mean, 3.3 ± SD, 1.3 yr; median 3 yr [range 2–5]). Metastases location is displayed in Table 2Go. Five patients (16.6%) died due to thyroid cancer 5.6 ± SD, 3.5 yr after initial surgery (median 7 yr [range 2–10]). Two other patients (6.6%) died from intercurrent disease.

Immunohistochemical analysis

Formalin-fixed and paraffin-embedded well-preserved tissue blocks from surgically thyroid resected specimens were used for the immunohistochemical study. The pathologist who reviewed the nm23-H1 staining was not the same who made the original diagnosis of neoplasia. In addition, he ensured that the sample under observation was really affected with DTC, and he was unaware of any of the clinical features of the patients.

For the immunostaining we used as a primary antibody a monoclonal antibody (clone 37.6), IgG2a, and the nucleoside diphosphate kinase A (NDPK-A) as the antigen for the immunization, purified from human erythrocytes (nm23-H1; Novocastra Laboratories Ltd., New Castle, UK). The antibody recognizes the human nm23-H1 protein (NDPK-A) and presents only a low cross-reaction with nm23-H2 (NDPK-B) homolog.

The 5-µm sections formalin-fixed, paraffin-embedded specimens were deparaffinized in xylene and rehydrated in decreasing concentrations of ethanol. Endogenous peroxidase activity was blocked with hydrogen peroxide 0.03% for 5 min. The slides were incubated with a 1:300 dilution of the primary monoclonal antibody at room temperature for 1 h. The sections were then incubated for 30 min with a biotinylated secondary antimouse antibody (DAKO Corp., Glostrup, Denmark). Diamino benzidine was used as a chromogen for color development. The slides were counterstained with hematoxylin. To minimize the staining variation, the same normal thyroid tissues were used as internal controls in each experiment.

Immunostainning results were assessed semiquantitatively, taking into account the percentage of nm-23 positive cancer cells that was estimated by counting 500 cells in 10 high-power fields. The patients were classified into two groups: cases with less than 10% nm23-H1 positive cancer cells were classified as "negative" and those with more than 10% (moderately or strongly stained) as "positive." This is a valid cut-off that has been previously used (38, 46). The cytoplasmic and nuclear staining were analyzed separately. Furthermore, staining intensity was compared with normal thyroid tissue adjacent to the tumor.

Statistical analysis

The relationships between nm23-H1 expression and baseline clinical variables displayed in Table 1Go were evaluated. In addition, the association between nm23-H1 and the evolutive variables such as local recurrences, distant metastases, and survival rate were explored. Statistical analysis was performed using {chi}2 test or Fisher exact test for categorical variables, and t test for continuous variables. The survival curves were constructed using the Kaplan-Meier method, and the comparisons between groups were performed by the log-rank test. Survival period was computed from the time of thyroidectomy until death. In the group of patients with follicular carcinoma, we performed a comparison between nm23 and AMES score (4) in terms of sensitivity, specificity, predictive values, and survival rate. A P value less than 0.05 was considered to be statistically significant. The quantitative data were given as mean ± SD.

Results

Normal thyroid epithelial cells were homogeneously stained (>10%) by the monoclonal anti-nm23-H1 antibody. In most cases the immunostaining was moderated to intense (>30%), thus making the possibility of false negative results very unlikely (Fig. 1Go).



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  		Figure 1. nm23-H1 immunostaining showing the difference between normal (positive) and tumoral thyroid tissue (negative).

 
Eighty-two of 94 (87.2%) malignant tissue specimens were positive for nm23-H1, and 12 (12.8%) were negatives. A large majority of the positive cases (95%) exhibited only a cytoplasmatic staining (Fig. 2AGo), and in 5 of them a membranous staining was also detected. In addition, a mild to moderate nuclear staining was observed in 4 cases (Fig. 2BGo).



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  		Figure 2. Two different patterns of nm23-H1 immunostaining corresponding to papillary thyroid carcinoma: cytoplasmatic positivity (top) and nuclear positivity (bottom).

 
Papillary carcinoma

Seven of the 64 patients (10.9%) were classified in the negative group and 57 (89.1%) in the positive one. We did not observe any relationship between nm23-H1 immunoreactivity and age, gender, initial DTC stage, local recurrence, or distant metastases (data not shown). The statistical comparison between Kaplan-Meier curves could not be performed in papillary cancers because the number of deaths was limited (only two cases).

Follicular carcinoma

Five of the 30 follicular cases (16.8%) showed negative nm23-H1 expression, whereas 83.2% were positive. No correlations were found between nm23-H1 immunoreactivity and age, gender, initial DTC stage, and local recurrence. However, we observed an inverse association between nm23-H1 expression and the development of distant metastases. Thus, 4 out of 5 negative patients (80%) developed distant metastases, whereas this event was only detected in 7 out of 25 positive patients (28%), (P < 0.05). The outcome of patients with follicular carcinoma according to nm23-H1 expression is shown in Fig. 3Go. As can be seen, nm23-H1 immunoreactivity was not only related to metastasic potential but also to mortality. The mean survival time from initial treatment to death in patients with metastases was notably lower in those nm23-H1 negatives than in nm23 positives [3.6 ± SD, 2.8; median 2 (2, 3, 4, 5, 6, 7) vs. 8.5 ± SD, 2; median 8 (7, 8, 9, 10) yr].



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  		Figure 3. Clinical outcome of patients with follicular carcinoma according to nm23-H1 immunostaining.

 
Kaplan-Meier survival curves showed that patients with nm23-H1 negative staining exhibited significantly lower rates of survival than those with positive immunoreactivity (log-rank P = 0.0031) (Fig. 4AGo). Thus, the 10-yr survival rate in patients with follicular thyroid carcinoma was 90% for those with nm23-H1 positive tumors but was only 40% for nm23-H1 negative cases.



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  		Figure 4. Kaplan-Meier survival curves after initial treatment according to nm23-H1 immunostaining (A) and Ames score (B).

 
To further evaluate the usefulness of nm23-H1 expression as a prognostic factor in follicular thyroid carcinoma we compared its sensitivity, specificity and predictive values to develop metastases and also the rate of mortality with the Ames score. This is a well recognized scoring system that has been also recently validated to classify those patients at high risk or low risk to develop metastases, not only in papillary (4) but also in follicular thyroid carcinomas (47). nm23-H1 was more specific but less sensitive than AMES to predict metastases (Table 3Go). In addition, Kaplan-Meier survival curves were more accurately fitted when using nm23-H1 (Fig. 4BGo).


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  		Table 3. Statistical analysis of the performance of the two systems (nm23-H1 immunostaining and AMES score) to anticipate metastatic evolution

 
Discussion

The management of DTC is a topic that generates conflicting views. Thus, some authors claim that due to its excellent prognosis most patients are suffering from overtreatment (i.e. total thyroidectomy, ablation of remnants with high doses of radioiodine) (48). However, other authors have shown that the best prognosis is achieved in patients receiving more aggressive treatment (49). In an attempt to further identify the patients at high risk to develop metastases and also to avoid unnecessary therapeutic procedures for many patients with good prognosis, different prognostic scoring systems based on clinical parameters have been proposed (3, 4, 5, 6, 7, 8). Recent progress in DNA sequencing techniques could be a useful tool to help in identifying this subset of patients at high risk to develop metastases. On this regard, nm23—a MSG gene—has been associated with low metastatic potential in some cancers. The product of the nm23 gene exhibits a nucleoside diphosphate kinase activity (50), but the molecular mechanism of the antimetastatic effect remains unknown.

In the present study nm23-H1 protein immunoreactivity was inversely associated with the metastatic potential and mortality in patients with follicular thyroid carcinoma. The predictive value to develop metastases in patients without significant expression of nm23-H1 was 80%. In addition, the 15-yr survival rate in patients with follicular thyroid carcinoma was 90% for those with nm23-H1 positive tumors but was only 40% for nm23-H1 negative cases. By contrast, nm23-H1 protein expression was not related to either metastases or survival rate in patients with papillary thyroid carcinoma. Therefore, a separate analysis taking into account the two types of DTC should be mandatory, at least when cohorts and follow-up periods similar to the present study are used. Our results suggest that the biological significance of nm23-H1 expression may be quite different not only in different tissues but also in different neoplasms of the same organ. Although derived from the same cell type as its follicular counterpart, papillary carcinoma shows a different biological behavior. Papillary carcinoma characteristically metastasizes to regional lymph nodes, whereas follicular cancer commonly spreads hematogeneously. Furthermore, there is a body of evidence suggesting that there are two distinct genetic pathways for papillary and follicular tumors (9).

There are a few studies addressed to investigate nm23-H1 expression in DTC, and the results are conflicting (37, 38, 39, 40, 41, 42, 43, 44). Arai et al. (37, 38) and Okubo et al. (44) reported that nm23-H1 expression was lower in metastatic lymph node tissue than in the primary tumor. Luo et al. (41) concluded that nm23-H1 gene product may not be a good predictive marker for regional metastasis in thyroid tumors. Zou et al. (43) found a direct correlation between gene expression and aggressiveness. Farley et al. (40) and Roy et al. (42) failed to observe any association between nm23-H1 expression and the outcome of the patients in their reports. Finally, Bertheau et al. (39) found a lack of association between cytoplasmatic or membranous expression of nm23-H1 and histological type of tumor or survival, but nuclear staining was associated with a longer disease-free survival. It should be noted that in these previous studies the number of patients included was low and most specimens were obtained from patients with papillary thyroid carcinoma, thus precluding an appropriate analysis for follicular tumors. To our knowledge, our series is the largest study of the nm23-H1 protein in primary tumors of DTC and the number of follicular tumors included as well as the follow-up period was enough to accurately explore the usefulness of nm23-H1 as a prognostic factor. Furthermore we have only analyzed samples from primary tumors of DTC, and we did not include specimens from metastases or local recurrences. This is an important point because the de-differentiation process of metastatic tissue could modify the expression of nm23-H1, thus acting as a confounding factor (37, 38, 39).

One is curious to ask what the analysis of nm23-H1 expression by immunocytochemistry would add to the clinical prognosis scores currently in use to predict the outcome of patients with follicular thyroid carcinoma. To answer this question, we have compared nm23-H1 immunoreactivity with AMES score in terms of sensitivity, specificity, predictive values, and survival rate. nm23-H1 was more specific but less sensitive than AMES. In addition, nm23-H1 immunostaining was a more appropriate predictor of survival rate. Interestingly, nm23-H1 offers new information that cannot be obtained by AMES score. Thus, two out of three patients at low risk according to AMES were actually identified as being at risk of metastasis by nm23-H1. Taken together, these findings suggest that nm23-H1 and AMES score are complementary as prognosis indices in patients with follicular thyroid carcinoma. It would be interesting to construct survival curves taking into account both AMES classification and nm23-H1 immunostaining (cytoplasmic or nuclear), but for this purpose a large cohort would be necessary.

In conclusion, our findings suggest that nm23-H1 is useful as a prognosis indicator in patients with follicular thyroid carcinoma and should be added to the classic prognostic factors currently used to identify those patients at risk to develop metastases.

Footnotes

This work was supported by Grant 99/1100 from the Fondo de Investigaciones Sanitarias, National Health Institute of Spain.

Abbreviations: DTC, Differentiated thyroid carcinoma; MSG, metastasis-suppressor genes; Tg, thyroglobulin; WBS, whole body scan.

Received November 8, 2000.

Accepted April 18, 2001.

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals