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Rearrangement Is Frequently Detected in the Follicular Variant of Papillary Thyroid Carcinoma
Institute of Molecular Pathology and Immunology of the University of Porto (P.C., A.P.R., R.J.S., J.M., V.T., M.C.-d.-O., E.F., P.S., M.S.-S.), 4200-465 Porto, Portugal; Department of Pathology (J.M., E.F., P.S., M.S.-S.), Medical Faculty of Porto, 4200-319 Porto, Portugal; Centro de Investigação de Patobiologia Molecular (L.R.), Instituto Português de Oncologia Francisco Gentil, 1070 Lisboa, Portugal; Department of Pathology (I.V.d.C.), Medical Faculty, University of São Paulo, 05509-900 São Paulo, Brazil; and Department of Surgery (M.C.-d.-O.), Medical Faculty of Porto, 4200-319 Porto, Portugal
Address all correspondence and requests for reprints to: Prof. M. Sobrinho-Simões, Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n4200, 465 Porto, Portugal. E-mail: ssimoes{at}ipatimup.pt.
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Abstract |
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Objective/Design/Patients: In an attempt to clarify such controversies and to find whether or not FVPTC cases share the molecular features of follicular tumors, we searched for the presence of PAX8-PPAR
rearrangements, RAS mutations, and RAP-1, RAF-1, and BRAF mutations in a series of 40 FVPTCs as well as in 27 follicular thyroid carcinomas (FTCs) and 12 follicular thyroid adenomas (FTAs). Fluorescence in situ hybridization and RT-PCR were used to detect the PAX8-PPAR rearrangement and PCR, single strand confirmational polymorphism, and sequencing for searching the mutations.
Results: The frequency of PAX8-PPAR rearrangement was similar in FVPTCs (37.5%), FTCs (45.5%), and FTAs (33.3%). The same holds true regarding the frequency and type of RAS mutations: FVPTC, 25.0%; FTC, 22.2%; and FTA, 33.3%. BRAF mutations were only detected in FVPTC (10%); the BRAF mutations in these cases (K601E and G474R) are different from the typical BRAFV600E mutation of conventional PTCs. No mutations were detected in RAP-1 and RAF-1. In FVPTCs, the PAX8-PPAR rearrangement was significantly associated with multifocality and vascular invasion, whereas the RAS mutations were significantly associated with the large tumor size. There were three cases of FVPTC, three FTCs and one FTA, harboring both PAX8-PPAR rearrangement and RAS mutations; patients with such tumors were usually very young.
Conclusions: We conclude that a subset of FVPTC shares some of the molecular features of follicular tumors. Further studies are necessary to clarify the putative clinical significance (e.g. association to blood-born metastases) of PAX8-PPAR rearrangement, RAS mutations, and BRAFK601E in FVPTCs.
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Introduction |
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PTCs are frequently multifocal, give rise to lymph node metastases, and carry an overall survival rate exceeding 90% after 10 yr (1, 2, 3). In contrast, FTCs are usually unifocal and encapsulated, tend to give rise to blood-born metastases, and carry a lower overall survival rate (1, 2, 3).
Cytologically, PTCs display characteristic nuclear changes (1, 2, 3). Tumors with the typical nuclear features of PTC that have a predominant or exclusive follicular growth pattern are classified as follicular variant of PTC (FVPTC) (3).
FVPTC cases, like most conventional PTCs, are slowly growing neoplasms that tend to give rise to lymph node metastases (1, 2, 3). In 1985, Carcangiu et al. (4) pointed out that, at variance with conventional PTC, some FVPTC cases were prone to give rise to lung metastases. It was observed, moreover, that the growth pattern of the encapsulated form of the FVPTC—there are two other forms of FVPTC in which the tumor growth pattern is poorly circumscribed or diffuse/multinodular and widely invasive (5, 6, 7)—mimicked that of FTC, pushing borders and signs of capsular and/or vascular invasion (1, 2, 3, 4, 8, 9). Baloch and LiVolsi (9) showed that these encapsulated FVPTCs may give rise to blood-born metastases in the absence of lymph node metastases.
It has been shown recently that FVPTC cases have a high percentage of RAS mutations (43%), which is similar to that observed in FTC (10), and contrasts with conventional PTC, in which such mutations were rarely detected (0–23%) (10, 11, 12, 13, 14).
The type and prevalence of BRAF mutations differ in FVPTCs from those detected in conventional PTCs (15). Conventional PTCs are characterized by the prevalent occurrence of BRAFV600E (46%) (15), whereas FVPTC cases have a different and less prevalent (10%) type of mutation (K601E) (15).
The PAX8-PPAR fusion gene has been detected in a high percentage of FTCs (16) and, later on, also in FTAs by several groups (17, 18, 19, 20). This fusion gene has not been detected in normal thyroid or nodular goiter, nor in any histological type of PTC (16, 17, 20). Despite this apparent specificity, Roque et al. (21) had described, using conventional cytogenetics, the t(2,3)(q13;p25) in one case of FVPTC. Moreover, Wreesmann et al. (22), using immunohistochemistry, demonstrated overexpression of peroxisome proliferator-activated receptor (PPAR) in three cases of FVPTC; in one of these cases, the presence of rearranged PPAR was detected by Southern blot (22). Finally, we have detected recently, in a preliminary study, the presence of the PAX8-PPAR rearrangement in four of eight cases of FVPTC (23).
In an attempt to find whether or not FVPTC cases share some of the molecular features of follicular tumors, we searched for the presence of PAX8-PPAR rearrangements, RAS mutations, and BRAF mutations in a series of 40 cases of FVPTC, as well as in two control series of 27 FTCs and 12 FTAs.
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Patients and Methods |
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The 40 cases of FVPTC included in the present study were exclusively or almost exclusively composed by follicles (papillary structures, if present, were observed in less than 5% of the tumor area; no psammoma bodies were observed in any case). Three of the 40 cases were composed by oxyphilic (Hürthle) cells. The diagnosis was based, in every case, on the typical PTC nuclei of the neoplastic cells (1, 2, 3). Besides the PTC-like nuclei, the tumors displayed pushing borders (with or without a well-defined capsule) and prominent foci of long and irregular follicles with scalloped colloid (1, 2, 3).
The treatment of the patients with FVPTC varied greatly from case to case and only rarely included lymphadenectomy. These limitations preclude the comparison of the cases regarding their lymph node metastatic potential. We also did not make any comparison regarding disease-free interval because the follow-up of most cases is too short. The same holds true for patients with FTC and FTA (see below).
The 39 follicular tumors were diagnosed as FTC (n = 27) and FTA (n = 12) according to the WHO classification (3). Eighteen of the 27 FTCs and eight of the 12 FTAs were composed by oxyphilic (Hürthle) cells. All but two FTC were diagnosed as minimally invasive FTC; cases 9 and 20 were diagnosed as widely invasive FTCs (3). There were signs of vascular invasion in 24 of the 27 FTCs; in the remaining three cases, the diagnosis was based upon unequivocal signs of capsular invasion (1, 2, 3).
Despite a thorough search, we did not detect vascular or capsular invasion in the 12 cases diagnosed as FTA. The limited number of histological sections available per case and the presence of equivocal signs of capsular and/or vascular invasion in some of the cases of FTA might lead, according to Williams (24), to their classification as follicular tumors of uncertain malignant potential. For the sake of simplicity, we decided to avoid this designation and to stick to the diagnosis of FTA.
Mutation screening
Genomic DNA was extracted from 10-µm paraffin-embedded tumor sections of 40 FVPTCs, 27 FTCs, and 12 FTAs. Slides were microscopically examined, and tumor areas were marked and carefully dissected under microscopic observation. Dissected material was deparaffinized in xylene, washed in ethanol, and rehydrated. DNA extraction was performed using the Genomic DNA Purification Kit (Gentra Systems, Inc., Minneapolis, MN) according to the manufacturer’s tissue protocol. Sequences of H-RAS (exons 1 and 2), K-RAS (exons 1 and 2), N-RAS (exon 2), BRAF (exon 11 and 15), RAF-1 (exon 15), and RAP-1 (exons 1–6) were amplified using primer pairs listed in Table 1
. All these analyses had not been performed previously but for the search of BRAF mutation in 32 cases of FVPTC (15) (Table 2). The PCR mixture (25 µl) contained 2.5 µl 10x Complete PCR Buffer (Bioron GmbH, Ludwigshafen, Germany), 1 µl dNTPs (5 mM each), 0.1 µg each primer, 0.1–0.5 µg genomic DNA, and 0.2 U Taq DNA Polymerase (Bioron GmbH). After 10 min of initial denaturation, the PCR mixtures were subjected to 35 cycles of denaturation for 30 sec at 95 C, annealing for 45 sec at variable temperature according to the amplicon (Table 1), and extension for 45 sec at 72 C. A final extension period of 10 min at 72 C was performed to finish the reaction.
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. Gels were silver stained, and samples with suspicious bands were purified by enzymatic treatment. Purified samples were sequenced on both strands as follows: 3 µl purified PCR product was added to 7 µl sequencing reaction containing 2.7 µl 2.5x Big Dye Buffer (Applied Biosystems, Foster City, CA), 30 ng primer, and 1 µl Big Dye terminator version 3.1 cycle (Applied Biosystems). Sequencing was performed in an ABI Prism 3100 Genetic Analyzer (Applied Biosystems). Mutated samples were reextracted, reamplified, and resequenced to confirm the result. In every SSCP analysis for the genes K-RAS, H-RAS, and BRAF, a positive control for the mutations was included. Because we did not have a positive control for mutations in RAP-1 and RAF-1 genes, we random selected and sequenced 10 FVPTCs and five FTCs for control purposes.
Fluorescence in situ hybridization (FISH)
FISH was performed on isolated nuclei extracted from 50-µm paraffin-embedded sections of 24 cases of FVPTC, 22 cases of FTC, nine cases of FTA, five samples of normal thyroid parenchyma (from five cases of FVPTC), two cases of conventional PTC, and four PTC-derived cell lines. Eight of the 24 FVPTC cases had been previously studied (23) (Table 2). Bacterial artificial chromosome (BAC) probes for PPAR (RPCI1130 G23, BAC PAC Resources; Alfagene, Carcavelos, Portugal) and PAX8 (RPCI 1165 I12, BAC PAC Resources) were used following the procedure of Marques et al. (25); the study was performed in the laboratory of Marques et al. (25) under the supervision of L. Roque, who is a coauthor of both papers. Briefly, PPAR BAC clone DNA was labeled with digoxigenin and PAX8 BAC clone DNA with biotin by random priming, using the Bioprime DNA labeling system (Invitrogen S.A., Barcelona, Spain). Nuclear suspensions were spotted on SuperFrost Slides (Menzel-Glaser, GMbH, Memmert, Germany) and pretreated with 0.1% pepsin (Sigma-Aldrich, St. Louis, MO) in 0.2% HCl at 37 C. Probe mixture in 50% formamide in 2x sodium saline citrate was codenatured with the nuclear DNA at 80 C for 2 min. Detection of digoxigenin-labeled PPAR probe was accomplished using an antidigoxigenin fluorescein antibody (Roche Diagnostics GmbH, Mannheim, Germany) and the biotinylated-labeled PAX8 probe with CY3-avidin (Jackson ImmunoResearch Laboratories Inc., West Grove, PA). Nuclei were counterstained with 4',6-diamidino-2-phenylindole-Vectashield mounting solution (Vector Laboratories, Burlingame, CA). Fluorescence hybridization signals were then analyzed and recorded with a Cytovison System (Applied Imaging, New Castle, UK). For each case, 200 intact nonoverlapping nuclei were counted. Nuclei in which the two probes were fused or touched were scored as positive for fusion gene.
RT-PCR
Total RNA was extracted from frozen samples of three tumors of the FVPTC using Tripure isolation reagent (Roche Diagnostics), according to the manufacturer’s protocol. cDNA was synthesized from 1 µg of RNA at 37 C for 90 min, using oligo (dT) primers and reverse transcriptase (Invitrogen). The presence of the PAX8-PPAR fusion gene was searched by RT-PCR as described previously (14).
Statistical analysis
The results are expressed as mean ± SD (age of the patients and size of the tumors), as percentage, or as absolute values. The 
2 test with Yate’s correction and the Student’s t test (unpaired) were used in the statistical analysis of the results. Values were considered significantly different when P < 0.05.
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Results |
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and 3 we have summarized the clinicopathological and molecular data of the 40 cases of FVPTC and those of the 39 follicular tumors (27 FTCs and 12 FTAs).
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The mean age ± SD was 44.4 ± 13.2 yr, and the mean size ± SD was 2.9 ± 1.8 cm. By FISH, we detected the PAX8-PPAR rearrangement in nine of the 24 cases that could be analyzed (37.5%) (Fig. 1 and Table 2). We confirmed the rearrangement, by RT-PCR, in the two cases in which frozen material was available. In five cases of rearranged FVPTC, the adjacent thyroid was analyzed by FISH, and the PAX8-PPAR rearrangement was not detected in any of the samples. The rearrangement also was not detected in the two cases of conventional PTC or in any of the four PTC-derived cell lines.
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rearrangement was significantly associated with the presence of multifocality (P = 0.027) and vascular invasion (P = 0.016). All the cases with vascular invasion, in which PAX8-PPAR analysis was performed (n = 3), had PAX8-PPAR rearrangement (Table 2). No significant association was found between the presence of PAX8-PPAR rearrangement and age of patients or size of tumors. We did not observe any consistent morphological difference, namely in the nuclear features, between cases with PAX8-PPAR rearrangement (n = 9) and cases without the rearrangement (n = 15).
RAS mutations were detected in 10 of the 40 cases (25%); six of the mutations were in N-RAS (Q61G) and four in H-RAS (Q61R) (Fig. 2 and Table 2). The cases harboring RAS mutations were significantly larger than those with wild-type RAS (P = 0.023). The presence of RAS mutations was not significantly associated with gender, age, multifocality, or invasion.
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and Table 2). In three cases, the mutation was the K601E; in the remaining case, it was a G474R mutation (Table 2). None of the four cases with BRAF mutation displayed signs of vascular invasion (Table 2). The presence of BRAF mutations was not significantly associated with any of the clinicopathological features. We did not observe any consistent morphological difference, namely in the nuclear characteristics, between cases with BRAF mutation (n = 4) and cases without mutation (n = 36).
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rearrangement and RAS and BRAF mutation. There were three cases of FVPTC harboring both PAX8-PPAR rearrangement and RAS mutation (patients with ages of 28, 29, and 55 yr) (Table 2). The BRAF mutation did not coexist with any of the other two alterations (Table 2). No mutations in RAP-1 and RAF-1 were detected in any case.
Follicular tumors
The mean age ± SD of patients with FTC was 49.1 ± 18.8 yr, and the mean age ± SD of patients with FTA was 41.5 ± 14.9 yr. The mean size ± SD of FTCs was 5.4 ± 3.2 cm, and the mean size ± SD of FTAs was 3.4 ± 1.8 cm. By FISH, we detected the PAX8-PPAR rearrangement in 10 of the 22 cases of FTC (45.5%) and in three of the nine cases of FTA (33.3%) (Table 3). The presence of PAX8-PPAR rearrangement was significantly associated with younger age of the patients in both FTCs (P = 0.039) and FTAs (P = 0.027).
RAS mutations were detected in six of the 27 cases of FTC (22.2%), four in N-RAS (Q61G), and two in H-RAS (Q61R). In FTA, we detected RAS mutations in four of the 12 cases (33.3%); three in N-RAS (Q61G) and one in HRAS (Q61R) (Table 3). No significant association was observed between the occurrence of RAS mutations and any of the clinicopathological features of the cases in the groups of FTC and FTA.
No significant differences were found in any of the markers analyzed in the comparison of FTAs and FTCs with and without oxyphilia (data not shown).
There were four cases harboring PAX8-PPAR rearrangement and RAS mutation; three FTCs and one FTA (Table 3). The FTC patients with both alterations were significantly younger than patients with tumors without any genetic alteration (P = 0.007). The single FTA with both genetic alterations (PAX8-PPAR rearrangement and RAS mutation) occurred in a 25-yr-old patient, thus fitting with the young age of patients with both alterations.
No mutations in BRAF, RAP-1, and RAF-1 were detected in any follicular tumor (26 FTCs and 12 FTAs).
Comparison between cases of FVPTC and follicular tumors
The frequency of PAX8-PPAR rearrangement is similar in FVPTCs (37.5%), FTCs (45.5%), and FTAs (33.3%). The frequency of RAS mutations is also similar in FVPTCs (25%), FTCs (22.2%), and FTAs (33.3%). The BRAF mutation was present in 10% of FVPTCs and was absent from FTCs and FTAs.
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Discussion |
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in FVPTCs and in follicular tumors. We report, for the first time, a large series of cases of FVPTC in which the PAX8-PPAR fusion gene has been detected in a high percentage of cases (37.5%). Our data support the preliminary data on record (21, 22, 23) and demonstrate that there is a strong association between the occurrence of PAX8-PPAR rearrangement and the follicular growth pattern even in the setting of PTC. The nuclear features of FVPTC were of the PTC-type regardless of the presence or absence of PAX8-PPAR rearrangement, thus supporting the assumption that such features probably reflect molecular alterations other than those related to the rearrangement.
The significant association we have found between PAX8-PPAR and multifocality and vascular invasiveness in the group of FVPTC suggests that the rearrangement confers a higher invasive potential. Furthermore, all the vascular invasive tumors studied for PAX8-PPAR had the rearrangement. These findings fit with those reported by Nikiforova et al. (26) in FTC and indicate that PAX8-PPAR-positive cases of FVPTC may be prone to give rise to blood-born metastases. The confirmation of this hypothesis requires the study of a large series of cases of FVPTC with and without the rearrangement.
The frequencies of PAX8-PPAR in FTCs (45.4%) and FTAs (33.3%) are in accordance with the data on record (16, 17, 18, 19, 20). Our results are also similar to those reported by Nikiforova et al. (26) regarding patients’ age; both in FTC and FTA, patients with tumors with PAX8-PPAR rearrangement were younger than patients with tumors without the rearrangement.
Because the vast majority of FTCs in our series were minimally invasive carcinomas, it was not possible to analyze the putative association of PAX8-PPAR rearrangement with overtly invasive features of the tumors, as advanced by Nikiforova et al. (26).
The second issue concerns the occurrence of RAS mutations, which were usually considered to be typical of follicular tumors and relatively rare in PTC (10, 11, 12, 13, 14). Recently, a high prevalence (43%) of (N)RAS mutations in FVPTC (10) has been reported. We detected RAS mutations in about 25% of the cases in both FVPTC and FTC and a slightly higher percentage in FTA (33.3%), with a predominance, in every group, of N-RAS Q61G. These data are in accordance with the data on record (10, 11, 12, 13, 14) and show that RAS is a target gene both in FVPTC and in follicular tumors and that there is no apparent difference in the frequency of mutations or in the type of mutations in these two types of tumors.
We observed that cases of FVPTC with RAS mutations were larger than cases with wild-type RAS; this finding concurs with the findings of Nikiforova et al. (26) in FTC. The absence of a similar association in our series of follicular tumors may be due to the small size of the sample and to the fact that almost all cases of FTC were minimally invasive carcinomas.
At variance with the advanced rarity of the coexistence of RAS mutations and PAX8-PPAR rearrangement (26), we detected both alterations in 12.5% cases of FVPTCs, 13.6% of FTCs, and 8.3% of FTAs. We observed, furthermore, that the presence of both alterations was significantly associated with a younger age of the patients, favoring that such coexistence may lead to more rapidly growing tumors.
Although it is not yet fully characterized the cellular impact of PAX8-PPAR in thyroid, it has been advanced that the suppressor role of PPAR in normal thyroid growth is impaired by the rearrangement (16). The observation that PAX8-PPAR rearrangements and RAS mutations can coexist in the same tumor and that the patients with tumors with PAX8-PPAR and RAS mutation are young suggest that these genetic alterations may have a cumulative effect in the tumorigenic potential and may activate distinct cellular pathways.
The third issue regards the occurrence of BRAF mutations. No mutations in BRAF hot-spot regions (exons 11 and 15) were detected in any of the follicular tumors. We had already pointed out the rarity of BRAF mutations in these tumors (27). Interestingly, in a series of 11 cases of FTA arising in the post-Chernobyl setting, the only case with a BRAF mutation had a K601E mutation (28), which is the mutation detected in three cases of FVPTC of the present series. The other BRAF mutation (G474R) has not been reported previously in any type of thyroid tumors or in other types of tumor, to the best of our knowledge.
Conventional PTC with papillary or mixed follicular/papillary growth pattern, as well as the tall cell variant, the Warthin-like PTC, and the oncocytic variant of PTC with a predominantly papillary growth pattern, frequently (46–75%) harbor the BRAFV600E (15), whereas the FVPTC, besides not harboring the V600E mutation, harbors in about 8% of the cases of the BRAFK601E.
Both types of mutations affect the activating segment of the protein, particularly the two adjacent residues (V600 and K601) that are localized between the two major phosphoregulatory residues (T599 and S602) (29). It was shown that the BRAFV600E has about 2.5x the kinase activity of BRAFK601E (30, 31) and that both mutations activate the BRAF/MEK/ERK pathway (31). It was also found that the V600E was the only type of BRAF mutation detected in 10–35% of poorly differentiated and undifferentiated thyroid carcinomas harboring BRAF mutations (32, 33, 34, 35). In summary, there is enough evidence to claim that the two types of BRAF mutation differ from each other both in vitro and in vivo, but the close phenotype-genotype relationship with regard to the architecture pattern of PTC remains unexplained.
The absence of detectable mutations in RAP-1 and RAF-1 genes in any of the tumor groups suggests that these genes are not a major target of mutations in FVPTC or in follicular tumors. These negative results should be taken with caution because we had no positive controls for RAP-1 and RAF-1 mutations.
The fourth issue concerns the putative relationship between FVPTC and conventional PTC on one side and FTC on the other. Taking our data on the high frequency of PAX8-PPAR rearrangement and (N)RAS mutations in FVPTC, together with the data on record on PTC and follicular tumors regarding RAS mutations (10), it seems logical to conclude that some cases of the FVPTC share some of the molecular features of follicular tumors (FTA and FTC).
This conclusion is reinforced by the finding of Wreesmann et al. (22) who showed, using comparative genomic hybridization analysis, that the presence and pattern of genomic aberrations in FVPTC were significantly different from those in conventional PTC and similar to those observed in follicular tumors (22).
The comparison of the morphological features of cases of FVPTC with and without PAX8-PPAR rearrangement, as well as with and without RAS and BRAF mutations, did not yield any discernible differences for diagnostic purposes. Therefore, it does not seem possible to rely upon histopathology for the identification of the subset of FVPTC that shows some of the molecular features of follicular tumors.
We think there is enough evidence to rule out the idea that FVPTC, as a whole, should be considered as a subgroup of conventional PTC (Fig. 4A), and we would favor, taking into consideration the metastatic pattern (4, 5, 6, 7, 8, 9) and the molecular features described in the present study, the concept represented schematically in Fig. 4B.
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rearrangement, RAS mutation, and BRAFK601E) per se, or in association, in FVPTC. It will be interesting to find out whether the tendency for blood-born metastases of some FVPTC may be ascribed to a particular molecular profile of the tumors, namely to the presence of PAX8-PPAR rearrangement (see above). In the affirmative case, we would suggest that such encapsulated FVPTCs with PAX8-PPAR rearrangement should be classified, for practical purposes, in the group of FTC rather than as a variant of PTC (Fig. 4C).
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Footnotes |
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First Published Online October 11, 2005
Abbreviations: BAC, Bacterial artificial chromosome; FISH, fluorescence in situ hybridization; FTA, follicular thyroid adenoma; FTC, follicular thyroid carcinoma; FVPTC, follicular variant of PTC; PPAR, peroxisome proliferator-activated receptor; PTC, papillary thyroid carcinoma; SSCP, single strand confirmational polymorphism.
Received June 16, 2005.
Accepted October 4, 2005.
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1 fusion oncogene in human thyroid carcinoma. Science 289:1357–1360 1 rearrangements in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 87:3947–3952 fusion oncogene in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 88:354–357 1 gene expression status in benign and malignant thyroid tissues. Eur J Endocrinol 151:367–374[Abstract] rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am J Surg Pathol 26:1016–1023[CrossRef][Medline] translocation. Int J Surg Pathol 13:235–238 in PAX8/PPAR-negative thyroid tumours. Br J Cancer 91:732–738[Medline] rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab 88:2318–2326This article has been cited by other articles:
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