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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 10 4595-4601
Copyright © 2002 by The Endocrine Society

Original Article

Chromosomal Aberrations by Comparative Genomic Hybridization in Hürthle Cell Thyroid Carcinomas Are Associated with Tumor Recurrence

Nobuyuki Wada, Quan-Yang Duh, Daishu Miura, Laurent Brunaud, Mariwil G. Wong and Orlo H. Clark

Endocrine Surgical Oncology Fellows (N.W., D.M., L.B.), Department of Surgery, University of California, San Francisco, and UCSF/Mount Zion Medical Center (M.G.W., O.H.C.), San Francisco, California 94143; Surgical Service, Veterans Affairs Medical Center (Q.-Y.D.), San Francisco, California 94121; First Department of Surgery (N.W.), Yokohama City University School of Medicine, Yokohama 236-0004, Japan; and Department of Endocrine Surgery (D.M.), Toranomon Hospital, Tokyo 105-8470, Japan

Address all correspondence and requests for reprints to: Orlo H. Clark, M.D., Department of Surgery, University of California, San Francisco/Mount Zion Medical Center, 1600 Divisadero Street, San Francisco, California 94143-1674. E-mail: clarko{at}surgery.ucsf.edu.

Abstract

Hürthle cell thyroid neoplasms are classified as variants of follicular neoplasms, but they have distinct clinicopathological features. Chromosomal aberrations by comparative genomic hybridization (CGH) are common in Hürthle cell neoplasms. However, there is currently only limited information concerning the relationship between the chromosomal aberrations by CGH and tumor behavior. We, therefore, investigated chromosomal aberrations in primary Hürthle cell neoplasms (13 carcinomas and 15 adenomas) using CGH and correlated the aberrations identified with tumor node metastasis (TNM) stage, tumor differentiation, capsular invasion, and tumor recurrence. Chromosomal aberrations were found in 62% (8 of 13) of carcinomas and 60% (9 of 15) of adenomas. Overall, common chromosomal gains were found on 5p (29%), 5q (36%), 7 (29%), 12p (14%), 12q (21%), 17p (29%), 17q (32%), 19p (32%), 19q (25%), 20p (21%), 20q (29%), and 22q (18%). Common chromosomal losses were found on 2q (18%) and 9q (18%). Thirty-eight percent (5 of 13) of carcinomas were TNM stage III, 31% (4 of 13) were moderately to poorly differentiated, and 46% (6 of 13) were intermediately to widely invasive. Recurrence occurred in 38% (5 of 13). Carcinomas that subsequently recurred had a greater number of chromosomal gains (9.0 vs. 1.3; <0.005) and had more frequent chromosomal gains on 12q, 19q, and 20p (<0.001), 5p, 7, 19p, and 20q (<0.005), and 12p (<0.01) than those that did not recur. Five of the eight (63%) patients with aberrations developed recurrence, whereas none of the five patients without aberrations developed recurrence. In conclusion, chromosomal gains by CGH on 5p, 7, 12p, 12q, 19p, 19q, 20p, and 20q in Hürthle cell carcinomas are associated with tumor recurrence. Such chromosomal aberrations may be predictive for recurrent disease in patients with Hürthle cell thyroid carcinoma.

HÜRTHLE CELL CARCINOMA of the thyroid accounts for approximately 3% of all thyroid cancers. Although Hürthle cell carcinomas are classified as variants of follicular neoplasms, they are more often multifocal and somewhat more aggressive and are less likely to take up iodine than other follicular neoplasms (1, 2, 3, 4, 5, 6). Some authors consider that all Hürthle cell neoplasms are malignant and should be treated accordingly (7, 8). Most authors, however, suggest that Hürthle cell neoplasms can be separated into benign (no capsular and vascular invasion) or malignant using similar criteria as used for follicular neoplasms (1, 2, 3, 9) and also suggest that Hürthle cell carcinomas do not necessarily carry an unfavorable clinical outcome (6, 10).

Genetic alterations in Hürthle cell neoplasms have been studied by various techniques, including DNA ploidy (11, 12, 13, 14), cytogenetic (karyotype), and fluorescence in situ hybridization (FISH; Refs. 15, 16, 17), and most recently by comparative genomic hybridization (CGH; Refs. 18, 19, 20). CGH studies have also identified chromosomal aberrations in papillary, follicular, medullary, and anaplastic thyroid carcinomas (18, 19, 21, 22, 23, 24, 25, 26, 27, 28). CGH enables the analysis of the entire genome for DNA copy number gains and losses and requires no prior information of particular chromosomal aberrations. Three prior studies using CGH showed Hürthle cell neoplasms to have frequent chromosomal aberrations. However, the relationship between chromosomal gains and losses by CGH, clinicopathological features, and tumor behavior is not well established.

We, therefore, investigated the frequency, number, and pattern of chromosomal aberrations in Hürthle cell neoplasms using CGH and correlated the presence of chromosomal aberrations with tumor histology and behavior. We hoped to determine whether chromosomal aberrations by CGH in Hürthle cell carcinomas would correlate with tumor stage and aggressiveness. Documenting specific chromosomal gains and/or losses by CGH may also help identify related genes that are responsible for the behavior of Hürthle cell carcinoma of the thyroid.

Patients and Methods

Patients and tumor specimens

Primary Hürthle cell neoplasms (13 carcinomas and 15 adenomas) from patients who underwent initial thyroidectomy at University of California, San Francisco (UCSF) Hospital or UCSF/Mount Zion Medical Center (San Francisco, CA) between 1987 and 1998 were snap-frozen in the operating room and stored at -80 C.

The frequency, number, and pattern of chromosomal aberrations in Hürthle cell neoplasms were investigated using CGH. The relationship between the chromosomal aberrations and the clinicopathological features of Hürthle cell carcinomas were analyzed to determine whether chromosomal aberrations would correlate with tumor node metastasis (TNM) stage, tumor differentiation, capsular invasion, and tumor recurrence.

All of the 13 patients with Hürthle cell carcinoma underwent total thyroidectomy and TSH suppression therapy. Eleven of the 13 patients (except cases 9 and 10) received ablation therapy with radioactive iodine as initial therapy. We defined recurrences as clinical documentation of recurrent disease and/or elevation of serum thyroglobulin in patients who were clinically free of disease for 6 months after initial therapy. We considered an elevated thyroglobulin as evidence of persistent or recurrent disease. This investigation was approved by The Committee of Human Research of UCSF.

DNA extraction

High molecular weight whole genomic DNA was isolated from frozen tumor specimens using a standard protocol (29) involving proteinase K digestion, phenol and chloroform extractions, and ethanol precipitation. The tumor specimens were obtained from an area within the capsule of the tumor, and representative sections of the tumor were used to confirm the histological diagnosis. In this study, Hürthle cell neoplasms were defined as tumors in which 70% or more of the neoplastic cells were Hürthle cells. The concentration of DNA was measured with a fluorometer.

Preparation of metaphase spreads

Metaphase spreads were prepared according to standard protocols from phytohemagglutinin-stimulated peripheral blood lymphocytes from a karyotypically normal male (30). Briefly, T lymphocytes in RPMI 1640 medium were stimulated with phytohemagglutinin and cultured for 3 d. The cells were then synchronized by treatment with 10-7 M methotrexate for 15 h to inhibit DNA replication, followed by 10-5 M thymidine for 5 h to release the cells synchronously from the methotrexate-induced block. Colcemid (1 µg/ml) was added during the final 30 min of thymidine release. Lymphocytes were fixed in methanol and acetic acid (3:1) and dropped on precleaned microscope slides. The slides were air-dried in a thermotron environmental chamber.

CGH

Tumor DNA and reference DNA were differentially labeled by nick translation with fluorescein-12 (FITC)-deoxyuracil triphosphate (dUTP; NEN Life Science Products Inc., Boston, MA) and Alexa Fluor 568–5-dUTP (Molecular Probes, Inc., Eugene, OR), respectively. The size of DNA fragments was adjusted from 500-2000 bp for hybridization, depending on the amount of DNA polymerases (Life Technologies, Inc., Gaithersburg, MD) and incubation time. Hybridization of differentially labeled test and reference DNAs to normal metaphase chromosomes was performed as described previously (31), with slight modifications using fluorochromes conjugated to dUTP for standard nick translation (30). Normal metaphase slides were denatured by incubating in 70% formamide, 2x SSC (1x SSC: 0.15 M NaCl, 0.015 M Na3-citrate, pH 7.0) at 73 C for 3–5 min and dehydrated in ethanol (70, 85, and 100%). The labeled test and reference DNA samples (200 ng each) were precipitated together with 20 µg of unlabeled Cot-1 DNA (Life Technologies, Inc.), which was used to block the binding of repeated DNA sequences. The DNA mixture was dissolved in 50% formamide, 10% dextran sulfate, and 2x SSC (pH 7.0), denatured at 73 C for 5 min, and applied onto denatured normal metaphase spreads. Hybridization was performed at 37 C for 3 d in a humid chamber. Posthybridization slides were washed three times in washing solutions (50% formamide, 2x SSC, pH 7.0) and once in 2x SSC at 45 C, and then washed once in 2x SSC, twice in a phosphate nonidet buffer (0.1 M Na2HPO4, 0.1 M NaH2PO4, 0.1% Nonidet P-40, pH 8.0), and once in distilled water at room temperature. The slides were counterstained with 10 µl of 0.4 µM 4', 6'-diamidino-2-phenylindole in an antifade solution.

Digital image acquisition and analysis

The three color images from metaphase spreads were acquired using a microscope (Nikon Microphot-SA equipped with a 60x DIC NA 1.4 objective; Nikon, Melville, NY) and MicroImager 1400 CCD camera (Xillix Technologies Corp., Richmond, British Columbia, Canada) and were analyzed using a Quantitative Image Processing System. Individual chromosomes were segmented, local background was subtracted, the medial axes were defined, and green and red fluorescence intensity profiles were calculated by integrating fluorescence values across the chromosome widths along the medial axes. Approximately six different metaphases were analyzed for each hybridization, and the results were combined statistically to show the mean and SD of the green to red ratio. The regions with a ratio of more than 1.2 were defined as chromosomal gains, and those with a ratio less than 0.8 were defined as chromosomal losses. The centromeric regions of chromosomes 1, 9, and 16 and the p-arm of acrocentric chromosomes 13, 14, 15, 21, and 22 were excluded from the analysis, because CGH analysis for these heterochromatic regions is unreliable. The X and Y chromosomes were also omitted from the present analysis, because the tumor specimens and normal reference DNA were not sex-matched in some cases.

Statistical analysis

Frequency (percentage) was defined as number of tumors with any chromosomal aberrations divided by total number of tumors examined. Number of chromosomal aberrations was defined as number of individual chromosomal gains or losses per tumor. Frequencies were compared using the {chi}2 test and Fisher exact probability test. Numbers of chromosomal aberrations were analyzed using the Mann-Whitney U test. Differences were considered significant when P value was less than 0.05.

Results

Clinical description

The clinicopathological features of the 13 Hürthle cell carcinomas are summarized in Table 1Go. Thirty-eight percent (5 of 13) of carcinomas were TNM stage III. Thirty-one percent (4 of 13) were moderately to poorly differentiated, and 46% (6 of 13) were intermediately to widely invasive. The disease recurred in 38% (5 of 13) of the patients (cases 5, 10, 11, 12, and 13).


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  		Table 1. Clinicopathological features of the patients with Hürthle cell thyroid carcinoma

 
Frequency and number of chromosomal aberrations

Chromosomal gains and losses by CGH in 13 Hürthle cell carcinomas and 15 Hürthle cell adenomas are summarized in Table 2Go and are illustrated in Fig. 1Go, A and B. Overall, chromosomal aberrations were identified in 62% (8 of 13) of the carcinomas and in 60% (9 of 15) of the adenomas. In the 13 carcinomas, the mean number of chromosomal gains and losses per tumor were 4.2 and 0.8, respectively. In the 15 adenomas, the mean number of chromosomal gains and losses per tumor were 2.1 and 0.7, respectively. Hürthle cell carcinomas had more chromosomal aberrations than Hürthle cell adenomas, but the differences were not significant.


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  		Table 2. Chromosomal gains and losses by CGH in 13 Hürthle cell thyroid carcinomas and 15 Hürthle cell thyroid adenomas

 


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  		Figure 1. Chromosomal aberrations by CGH in 13 Hürthle cell thyroid carcinomas (A) and 15 Hürthle cell thyroid adenomas (B). Lines to the right of each chromosome ideogram show regions of increased relative DNA copy number (chromosomal gains), and lines to the left show regions of decreased relative DNA copy number (chromosomal losses).

 
Common chromosomal aberrations in carcinomas and adenomas

The frequencies of chromosomal aberrations by CGH on each chromosome are shown in Table 3Go. Overall, common chromosomal gains were found on 5p (29%), 5q (36%), 7 (29%), 12p (14%), 12q (21%), 17p (29%), 17q (32%), 19p (32%), 19q (25%), 20p (21%), 20q (29%), and 22q (18%). Common chromosomal losses were found on 2q (18%) and 9q (18%). Among the common aberrations, 12p gain was present only in carcinomas. Whole chromosomal gains were identified on chromosomes 5 (4 cases), 7 (4 cases), 12 (4 cases), 13 (2 cases), 17 (4 cases), 18 (1 case), 19 (4 cases), and 20 (3 cases) in the 13 carcinomas, and on chromosomes 5 (2 cases), 7 (2 cases), 17 (1 case), and 20 (1 case) in the 15 adenomas. Chromosomal gains were most common at 5p, 5q35, 7p21.3-pter, 7q36, 12p, 12q13-q21.31, 17p13, 17q24.3-pter, 19p13.3, 19q.13.3, 20p12.1-pter, and 20q13.3, and chromosomal losses were most common at 2q24.3-q31.1 and 9q13-q21.31 in both carcinomas and adenomas.


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  		Table 3. Frequency of chromosomal aberrations in 13 Hürthle cell thyroid carcinomas and 15 Hürthle cell thyroid adenomas

 
Frequency and number of chromosomal aberrations and clinicopathological features

Table 4Go shows that clinicopathological features of carcinomas are related to the frequencies and numbers of chromosomal aberrations by CGH. Intermediately to widely invasive carcinomas were more likely to have chromosomal aberrations (100% vs. 29%; <0.05) and had more chromosomal gains (7.2 vs. 1.7; <0.05) than minimally invasive carcinomas. Moderately to poorly differentiated carcinomas also had more chromosomal gains than well differentiated carcinomas (8.0 vs. 2.6; <0.05). Furthermore, TNM stage III carcinomas had more chromosomal gains than TNM stage I or II carcinomas (8.4 vs. 1.6; <0.005). Hürthle cell carcinomas that subsequently recurred also had more chromosomal gains than those that did not recur (9.0 vs. 1.3; <0.005). Chromosomal losses did not differ significantly among the carcinomas with different clinicopathological features.


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  		Table 4. Clinicopathological features of Hürthle cell thyroid carcinomas influence frequency of chromosomal aberrations and number of chromosomal gains and losses

 
Common chromosomal aberrations and clinicopathological features

Table 5Go summarizes the common chromosomal aberrations by CGH in Hürthle cell thyroid carcinomas with different clinicopathological features. Chromosomal gains on 5p, 7, and 19p (<0.005), and on 5q, 12q, 19q, and 20p (<0.05) were more common in TNM stage III carcinomas than in TNM stage I or II carcinomas. Chromosomal gains on 12q, 19q, and 20p (<0.001), 5p, 7, 19p, and 20q (<0.005), 12p (<0.01), and 5q (<0.05) were more common in carcinomas that subsequently recurred than in those that did not recur. Thus, five of the eight (63%) patients with chromosomal aberrations by CGH developed recurrence, whereas none of the five patients without chromosomal aberrations by CGH developed recurrence (Tables 1Go and 2Go). Chromosomal gains on 5p, 7, and 19p were more common in moderately to poorly differentiated carcinomas than in well differentiated carcinomas and in intermediately to widely invasive carcinomas than in minimally invasive carcinomas (<0.05).


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  		Table 5. Common chromosomal aberrations by CGH in Hürthle cell carcinomas with different clinicopathological features

 
Discussion

We used CGH to analyze the frequency, number, and pattern of chromosomal aberrations in Hürthle cell neoplasms of the thyroid and correlated the chromosomal aberrations in Hürthle cell carcinomas with clinical stage and tumor behavior.

We found chromosomal aberrations to be common in both carcinomas (62%) and adenomas (60%). This is similar to previous CGH studies (18, 19, 20). Hemmer et al. (18) found that three of four Hürthle cell adenomas had chromosomal aberrations. Frisk et al. (19) reported that three of four Hürthle cell carcinomas and two of three Hürthle cell adenomas had chromosomal aberrations. Tallini et al. (20) also found that three of four Hürthle cell carcinomas and six of seven Hürthle cell adenomas had chromosomal aberrations. The latter study was the first to focus on chromosomal abnormalities by CGH only in Hürthle cell neoplasms. This frequency of chromosomal aberrations found by CGH in Hürthle cell neoplasms is similar to that found in previous studies using FISH (16, 17). Although we found that carcinomas have more chromosomal gains and losses than adenomas, the differences are not statistically significant. These results are again similar to prior CGH studies (19, 20).

We found that whole or focal gains on chromosomes 5, 7, 12, 17, 19, and 20, and losses on chromosomes 2 and 9 were common in both Hürthle cell carcinomas and adenomas. These common aberrations have also been noted in previous studies using CGH (18, 19, 20). Furthermore, we identified 5p, 5q35, 7p21.3-pter, 7q36, 12q13-q21.31, 17p13, 17q24.3-pter, 19p13.3, 19q.13.3, 20p12.1-pter, and 20q13.3 as the most common regions for chromosomal gains, and 2q24.3-q31.1 and 9q13-q21.31 as the most common regions for chromosomal losses. Frisk et al. (19) also found that loss of 9q13-q21.3 was common for Hürthle cell carcinomas.

Gains of chromosome 5, 7, 12, and 17 were common in Hürthle cell thyroid neoplasms studied by karyotype and/or FISH (15, 16, 17). Trisomy 7 is considered the most common aberration in thyroid tumors and in several other tumors (15, 16, 17, 32, 33, 34, 35). Trisomy 7 was thought to cause other chromosomal aberrations in benign thyroid tumors (32). The incidence of trisomy 7, parallels the age distribution of patients with thyroid neoplasm and peaks at age 21–40 yr (33). Trisomy 12 is another common chromosomal aberration found in thyroid tumors by karyotype and/or FISH (15, 16, 17, 34, 35). The incidence of trisomy 7 and 12 increases as follicular cells progress from hyperplasia to benign and to malignant neoplasms, suggesting multistep progression for tumorigenesis (15). In our study, gains on chromosome 12 are more common in Hürthle cell carcinomas than in Hürthle cell adenomas, especially in patients with recurrent disease (12p, <0.01; and 12q, <0.001). The pattern of chromosomal aberrations (gains of chromosomes 5, 17, 19, and 20) in Hürthle cell neoplasms is similar to that found in follicular neoplasms in other studies using karyotype, FISH, and/or CGH (16, 17, 18, 19, 20, 23, 34). These data suggest that Hürthle cell neoplasms and follicular neoplasms have relatively similar genetic alterations.

Chromosome 19 may have a specific etiological role for Hürthle cell neoplasms. Familial Hürthle cell neoplasms have been linked to the TCO gene (thyroid tumors with cell oxyphilia), which is found on chromosome 19p13.2 by linkage analysis (36, 37). We did not have any familial occurrence, but we did find gains of chromosome 19 to be associated with tumor recurrence.

In contrast to previous studies, we analyzed the relationship between the chromosomal aberrations and the clinicopathological features of Hürthle cell carcinomas. We found that TNM stage III carcinomas and carcinomas that subsequently recurred had more chromosomal aberrations than their counterparts (Tables 4Go and 5Go). They differ in the number of chromosomal gains (<0.005), but not in the number of chromosomal losses. TNM stage III carcinomas have more frequent chromosomal gains on 5p, 7, and 19p (<0.005), and on 5q, 12q, 19q, and 20p (<0.05) than lower stage carcinomas. Chromosomal gains on 12q, 19q, and 20p (<0.001), 5p, 7, 19p, and 20q (<0.005), 12p (<0.01), and 5q (<0.05) are associated with tumor recurrence in patients with Hürthle cell carcinoma. Gains on 5p, 7, and 19p (<0.05) are also associated with tumor differentiation and capsular invasion.

All five TNM stage III carcinomas (from patients 2, 5, 11, 12, and 13) had numerical chromosomal aberrations by CGH; however, chromosomal gain of 1q was found only in patient 13, who developed distant metastases and died of disease (Tables 1Go and 2Go). Although this has not been described before for Hürthle cell carcinomas, Kjellman et al. (28) also found gains of 1q to be associated with distant metastasis in papillary thyroid carcinomas. A 1q gain may also be related to the adverse behavior of Hürthle cell thyroid carcinoma in some patients.

Loss of chromosome 22 in thyroid tumors was reported to be common and to worsen prognosis (16, 17, 18, 23, 34). Loss of chromosome 22 was more common in widely invasive follicular carcinomas (18) and was associated with death in patients with Hürthle cell carcinoma (17). However, we could not confirm these observations.

Our investigation suggests that the presence of chromosomal aberrations by CGH may predict the risk of tumor recurrence in patients with Hürthle cell carcinoma of the thyroid. Five of our eight (63%) patients with chromosomal aberrations developed recurrence, whereas none of our five patients without chromosomal aberrations developed recurrence. In a study of four patients with Hürthle cell carcinoma, Tallini et al. (20) previously found three carcinomas to have chromosomal aberrations by CGH. Two of these three patients had lung metastasis, and one died of disease, whereas the remaining patient, who had a carcinoma without chromosomal aberrations, did not develop recurrent disease. The two patients with lung metastasis had both 19q and 20p gains, which were more significantly associated with tumor recurrence (<0.001) than other chromosomal gains in our study.

We do not know why recurrent Hürthle cell carcinoma is associated with specific chromosomal aberrations, whether these aberrations are consequences of chromosomal instability of aggressive carcinoma, or whether the aberrations are the causes of the aggressive behavior.

Moreover, our results suggest that the degree of capsular invasion of Hürthle cell carcinoma may be a better predictor of tumor recurrence because four of the five patients (80%) with widely invasive carcinoma had recurrence of disease (Table 1Go). TNM stage and tumor differentiation may be another good indicator for tumor recurrence in some patients because 60% of TNM stage III carcinomas or 75% of moderately to poorly differentiated carcinomas recurred (Table 1Go). Our CGH results also suggest that the presence and the pattern of chromosomal aberrations may predict the risk of recurrence. One patient with only minimal capsular invasion had a recurrence, and this tumor had numerical chromosomal aberrations by CGH. Correlating the CGH results with each pathological feature, therefore, would be useful for the prediction of tumor behavior and also the extent of treatment. Further studies on more tumors will be needed to determine whether CGH results will be helpful to predict cancer behavior beyond what can be achieved with histological findings alone.

Previous studies suggest that the size of Hürthle cell neoplasm can be predictive of malignancy or tumor behavior (6, 38). We found that local invasion of Hürthle cell carcinoma (T4, tumor extends beyond thyroid capsule) was associated with the number of chromosomal aberrations by CGH. We did not, however, find any consistent relationship between the size of Hürthle cell carcinoma or adenoma and chromosomal aberrations (data not shown).

In conclusion, chromosomal aberrations, as studied by CGH, are common in both Hürthle cell carcinomas and adenomas. TNM stage III carcinomas and carcinomas that subsequently recurred had a greater number of chromosomal gains than lower stage carcinomas or those that did not recur (<0.005). Chromosomal gains on 12q, 19q, and 20p (<0.001), 5p, 7, 19p, and 20q (<0.005), 12p (<0.01), and 5q (<0.05) were significantly associated with tumor recurrence in patients with Hürthle cell carcinoma of the thyroid.

Acknowledgments

Footnotes

This work was supported in part by Mount Zion Health Systems, The James Martin Foundation, The Sanford Diller Foundation, The Helles Family Foundation, and The Friends of Endocrine Surgery.

Abbreviations: CGH, Comparative genomic hybridization; dUTP, deoxyuracil triphosphate; FISH, fluorescence in situ hybridization; TNM, tumor node metastasis.

Received March 4, 2002.

Accepted July 1, 2002.

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