Annals of Surgical Oncology 14(10):3011–3018
DOI: 10.1245/s10434-007-9503-8
Anaplastic Carcinoma of the Thyroid Arising More Often from Follicular Carcinoma than Papillary Carcinoma Hwei-Ming Wang, MD,1 Yu-Wen Huang, MS,2 Jen-Seng Huang, MD,3 Cheng-Hsu Wang, MD,3 Victor C. Kok, MD,4 Chao-Ming Hung, MD,5 Han-Ming Chen, MD,6 and Chin-Yuan Tzen, MD, PhD7,8,9
1
Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General Hospital, No. 160, Sec. 3, Chungkang Road, Taichung, Taiwan 2 Department of Medical Research, Mackay Memorial Hospital, No. 45, Minsheng Road, Tamshui, Taipei, Taiwan 3 Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, No. 222, Maijin Road, Keelung, Taiwan 4 Division of Medical Oncology, Kuang Tien General Hospital, No. 117, Shatian Road, Shalu, Taichung, Taiwan 5 Department of General Surgery, E-da Hospital, No. 1, Yida Road, Yanchau, Kaoshiung, Taiwan 6 Department of Surgery, Ten-Chan Hospital, No. 155, Yanping Road, Chungli, Taoyuan, Taiwan 7 Department of Pathology, Mackay Memorial Hospital, No. 45, Minsheng Road, Tamshui, Taipei, Taiwan 8 Mackay Medicine, Nursing and Management College, No. 92, Shengjing Road, Beitou, Taipei, Taiwan 9 National Taipei College of Nursing, No. 365, Minte Road, Beitou, Taipei, Taiwan
Background: Anaplastic thyroid carcinoma (ATC), a rare and highly malignant tumor, has long been thought to arise from well-differentiated carcinoma (WDC) such as follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC). The purpose of this study was to test this notion by examining whether and, if so, how often ATC harbors the oncogenes that are commonly associated with WDC, such as RAS in FTC and BRAF in PTC. Methods: We analyzed the mutation hotspots of BRAF (codon 600) and N-, K-, and HRAS (codons 12, 13, and 61) in 16 ATCs. We also examined two genes, PIK3CA (exons 9 and 20) and TP53 (exons 5–9), both of which have been reported in ATCs. Results: The results showed that approximately 31% (5 of 16) of ATCs harbored N-RAS mutation, 6% (1 of 16) had mutated BRAF, and approximately 56% (9 of 16) had mutated TP53. As to the three ATCs that had coexisted PTCs, mutated BRAF was detected in all PTC components but only in one ATC, while mutated PIK3CA was found in only one PTC component but not in the ATC. Conclusion: A number of ATCs arise from WDCs, more often from RAS-mutant tumors than from BRAF-mutant tumors, implying that particular attention should be paid to the WDC harboring RAS mutation. Key Words: Anaplastic thyroid carcinoma—Follicular thyroid carcinoma—Papillary thyroid carcinoma—BRAF mutation—N-RAS mutation—TP53 mutation.
Thyroid carcinoma is the most common malignancy of the endocrine system, accounting for the majority of deaths from endocrine cancers.1,2 Papillary thyroid carcinoma (PTC), including the follicular variant of PTC (FVPTC), accounts for 70–85% of the thyroid cancers, whereas follicular thyroid carcinoma
Received April 25, 2007; accepted June 4, 2007; published online: July 20, 2007. Address correspondence and reprint requests to: Chin-Yuan Tzen, MD, PhD; E-mail:
[email protected] Published by Springer Science+Business Media, LLC 2007 The Society of Surgical Oncology, Inc.
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(FTC) and anaplastic thyroid carcinoma (ATC) constitute 5–10% and 2–5%, respectively.3 PTCs, FVPTCs, and FTCs are included in a collective category termed well-differentiated carcinoma (WDC) and are characterized by their low aggressive behavior. Regardless of multimodal treatment including surgery, radiation therapy, and chemotherapy, few patients with ATC survive longer than 1 year, resulting in 1–7% 5-year survival rate. There are no known risk factors for the development of ATCs except for the observation that some ATCs are accompanied by WDC component.4 Such an association has led to a speculation that 1 or 2% of WDCs will develop into ATCs.4 However, the presence of preexisting or coexisting WDC in ATCs does not necessarily link their relationship in histogenesis. Concurrence of ATC and WDC in the same mass can be a random event, not unlike the finding of incidental PTC in a nodular goiter. Therefore, it remains to be determined whether ATC and WDC are related in histogenesis. Both FTCs and PTCs are thought to result from thyroid follicular epithelial cells through different oncogenic transformations in that mutation of BRAF and RAS, for example, preferentially occurs in PTC and FTC, respectively. More specifically, BRAF mutation is commonly identified in typical PTCs but is uniformly absent in FTCs.5–9 In contrast, mutations in N-RAS, K-RAS, H-RAS have been found in up to 50% of follicular neoplasms10 but are uncommon in PTC11,12 except FVPTC.13 The differential occurrence of these mutated oncogenes in different subtypes of WDC provides us a basis of using them as molecular markers to examine if ATCs are derived from WTCs and, if so, to determine which type of WDC attributes to most ATCs. To clarify the relationship between ATCs and WDC, we evaluated ATC and, when present, the associated WDCs for the mutations of BRAF, N-, K-, and HRAS. We also analyzed TP53 and PIK3CA because their mutations have been reported in ATCs.14,15 Through the understanding of the histogenesis of ATC, a more aggressive treatment can be directly applied to WDCs that are prone to develop into ATCs.
MATERIALS AND METHODS Specimen Selection, DNA Extraction, and RNA Isolation This study included 12 ATCs diagnosed in Mackay Memorial Hospital between 1994 and 2004, two from Kuang Tien General Hospital, one from E-Da Hospital, Ann. Surg. Oncol. Vol. 14, No. 10, 2007
and one (prepared in cell culture) from Chang Gung Memorial Hospital. Histologic slides were independently reviewed by two surgical pathologists, who confirmed the diagnosis. This study was approved by the Institutional Review Board of Mackay Memorial Hospital. DNA was isolated from formalin-fixed paraffinembedded tumors according to previously described procedures.16 In brief, representative paraffin blocks of formalin-fixed tumor were cut at 8 lm using a clean disposable microtome blade for each block. To ensure representative sampling, excess tissue was trimmed before sectioning. For cases No. 8, 10, and 13 that had both ATC and PTC, we used two paraffin blocks, one for each component. Furthermore, we checked the first and last section from each ribbon under light microscope after routine hematoxylineosin staining and proved that the two components were physically separated. The paraffin sections were transferred directly into the polymerase chain reaction (PCR) tubes and incubated in 300 lL xylene at 25C for 5 minutes, pelleted at 12,000 g for 5 minutes, resuspended in 300 lL of absolute alcohol at room temperature, spun down, and then lyophilized. The pellets were then processed using Puregene DNA isolation kit (Gentra, Minneapolis, MN, USA) according to manufacturerÕs instruction. The total RNAs were extracted from five sections, each 10 lm in thickness, using PURESCRIPT RNA Isolation Kit (Gentra, Minneapolis, MN). PCR, RT-PCR, and DNA Sequencing PCR was carried out in a reaction mixture containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 2 mM MgCl2, 0.2 mM deoxynucleotide triphosphate mix, 0.2 lM of each primer, 5 lL cDNA, and 1.25 U AmpliTaq Gold DNA polymerase (Applied Biosystems, Foster City, CA). The PCR reaction was performed with the thermal cycler GeneAmp PCR System 9700 (Applied Biosystems, Foster City, CA). The primers used for amplification and PCR conditions are listed in Table 1. For RT-PCR, RNA was reverse transcribed by incubation for 1 hour at 42C in the presence of 200 U of MMLV reverse transcriptase (Advantage RTfor-PCR kit, CLONTECH, CA) in 20 lL RT buffer containing 50 mM Tris-HCl (pH 8.3), 75 mM KCl, 3 mM MgCl2, 0.5 mM deoxynuclotide triphosphate mix, and 20 pmol of random hexamers. The PCR products were sequenced using the ABI PRISM BigDye Terminator v3.1 Cycle Sequencing Kit and 3730 DNA Analyzer (Applied Biosystems, Foster City, CA, USA).
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TABLE 1. Oligonucleotide primers and PCR conditions Amplicon size (bp)
Gene (exon)
Primer sequence
BRAF exon15
5¢-AAACTCTTCATAATGCTTGCTCTG-3¢ 5¢-AACTCAGCAGCATCTCAGGG-3¢ 5¢-TCTGTTCACTTGTGCCCTGA-3¢ 5¢-CAACCAGCCCTGTCGTCTCT-3¢ 5¢-CAAGCAGTCACAGCACATGA-3¢ 5¢-GACAACCACCCTTAACCCCT-3¢ 5¢-CCTCATCTTGGGCCTGTGTT-3¢ 5¢-CCAGGGGTCAGCGGCAAGCA-3¢ 5¢-ACTGCCTCTTGCTTCTCTTT-3¢ 5¢-AAGTGAATCTGAGGCATAAC-3¢ 5¢-GGAAGAGAATCTCCGCAAGA-3¢ 5¢-GAAAACGGCATTTTGAGTGT-3¢ 5¢-TTGCTTTTTCTGTAAATCATCTGTG-3¢ 5¢-CCACAAATATCAATTTACAACCATTG-3¢
TP53 exon5 TP53 exon6 TP53 exon7 TP53 exon8 TP53 exon9 PI3K exon9
PI3K exon20 H-Ras exon2 H-Ras exon3 K-RAS exon2 K-RAS exon3 N-RAS exon2 N-RAS exon3
5¢-TGACATTTGAGCAAAGACCTG-3¢ 5¢-CCTATGCAATCGGTCTTTGC-3¢ 5¢-GGCAGGAGACCCTGTAGGAG-3¢ 5¢-GTATTCGTCCACAAAATGGTTCT-3¢ 5¢-CTACCGGAAGCAGGTGGTCA-3¢ 5¢-CGCATGTACTGGTCCCGCAT-3¢ 5¢-GACTGAATATAAACTTGTGG-3¢ 5¢-CTATTGTTGGATCATATTCG-3¢ 5¢-TTCCTACAGGAAGCAAGTAG-3¢ 5¢-CACAAAGAAAGCCCTCCCCA-3¢ 5¢-CAGGTTCTTGCTGGTGTGAA-3¢ 5¢-CTCTATGGTGGGATCATATT-3¢ 5¢-TCTTACAGAAAACAAGTGGT-3¢ 5¢-ATACACAGAGGAAGCCTTCG-3¢
249 274 315 207 236 297 487
430 144 101 106 127 131 129
PCR condition 40 cycles: 15 seconds at 94C, 30 seconds at 55C, 45 seconds at 72C 40 cycles: 15 seconds at 94C, 30 seconds at 55C, 45 seconds at 72C 40 cycles: 15 seconds at 94C, 30 seconds at 55C, 45 seconds at 72C 40 cycles: 15 seconds at 94C, 30 seconds at 55C, 45 seconds at 72C 40 cycles: 15 seconds at 94C, 30 seconds at 55C, 45 seconds at 72C 40 cycles: 15 seconds at 94C, 30 seconds at 55C, 45 seconds at 72C Touchdown 10 cycles: 30 seconds at 94C, 45 seconds at 63–59C, 45 seconds at 72C; 30 cycles: 30 seconds at 94C, 45 seconds at 58C, 45 seconds at 72C 40 cycles: 30 seconds at 94C, 45 seconds at 60.7C, 45 seconds at 72C 40 cycles: 45 seconds at 94C, 45 seconds at 55C, 45 seconds at 72C 40 cycles: 45 seconds at 94C, 45 seconds at 55C, 45 seconds at 72C 40 cycles: 45 seconds at 94C, 45 seconds at 55C, 45 seconds at 72C 40 cycles: 45 seconds at 94C, 45 seconds at 55C, 45 seconds at 72C 40 cycles: 45 seconds at 94C, 45 seconds at 55C, 45 seconds at 72C 40 cycles: 45 seconds at 94C, 45 seconds at 55C, 45 seconds at 72C
PCR, polymerase chain reaction.
TABLE 2. Summary of mutational analysis of 16 thyroid anaplastic carcinoma Anaplastic carcinoma Case No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Papillary carcinoma
TP53
BRAF
N-RAS
PIK3CA
R158L Intron 5 A13318G – R158H – R248W – Q317STOP – Y263C E285K – R282W – – R273C
– – – – – – – – – – – – V600E – – –
Q61R – – – Q61R Q61R – – Q61R – – Q61R – – – –
– – – – – – – – – – – – – – – –
RESULTS A total of 15 surgically excised ATCs and one ATC cell line were analyzed in this study (Table 2). The age of these patients (3 males and 13 females) ranged
TP53
BRAF
N-RAS
PIK3CA
–
V600E
–
E545K
–
V600E
–
–
–
V600E
–
–
54–88 years. Every patient presented de novo with a thyroid mass that was ATC without a history of WDC. All patients died within 14 months (range 6– 412 days) after operation. Seven patients developed distant metastasis, and one of them had tumor Ann. Surg. Oncol. Vol. 14, No. 10, 2007
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FIG. 1. Microscopic features (hematoxylin-eosin staining) of thyroid anaplastic carcinoma show the presence of spindle (A, 100·) and squamoid tumor cells (B, 100·) (case No. 4). Some cases may have typical anaplastic carcinoma (right panel in C, 40·) accompanied by a component of papillary carcinoma (left panel in C, 40·; and D, 400·) (case No. 8).
recurrence before death. The histopathological evaluation of the anaplastic carcinoma showed spindle tumor cells. Focal squamoid differentiation (Fig. 1A) was identified in four tumors and was more common in males (3 of 3) than in females (1 of 13) (P = .007, Fisher exact test). Analyzing BRAF and PIK3CA showed that all three papillary carcinomas harbored BRAF mutation (Fig. 2A), and one had an additional PIK3CA mutation (Fig. 2B). In contrast, among the three ATCs accompanied by papillary carcinoma, only one had mutated BRAF and none had mutated PIK3CA. For the remaining 13 ATCs that were not associated with coexisting PTC, all were free of BRAF mutation. For N-RAS, H-RAS, and K-RAS analyses, we sequenced the regions encompassing codons 12, 13, and 61 and found that mutation only occurred at the codon 61 of N-RAS (Fig. 2C). This mutation was seen in five of ATCs, none of which were associated with coexisting PTC. For TP53, we analyzed exons 5–9 including the adjacent exon–intron junctions. The result showed that 9 of 16 ATCs harbor TP53 mutation (Table 2), including 7 missense mutations, 1 nonsense mutation, and 1 point mutation affecting the 3¢ splice junction of intron 5 (Fig. 3A). The splicing mutation was revealed by the presence of an alternative splicing product (Fig. 3B) and further substantiated by sequencing the eluted bands. Among these TP53 mutated ATCs, two had mutated N-RAS and 1 had mutated BRAF (Table 2). Ann. Surg. Oncol. Vol. 14, No. 10, 2007
None of these gene mutations were significantly associated with clinical features or pathological characteristics.
DISCUSSION Because ATCs are sometimes accompanied with WDCs, it has long been speculated that ATCs are dedifferentiated from the preexisting or coexisting WDCs. Recent advances in molecular biology provide us a tool to test this hypothesis. More specifically, we used the oncogenes commonly occurring in WDCs as molecular markers to trace the origins of ATCs, and we found that approximately 38% ATCs had either BRAF or RAS mutations. Although ATC could de-differentiated from either PTC or FTC, PTC is likely to be the major source because PTC is approximately eight times more common than FTC. However, BRAF mutation, the most common genetic defects in PTCs, was detected only in 1 of 16 ATCs in our series. Even for the three anaplastic carcinomas that were associated with BRAF-mutant PTC components, two of the ATCs were free of BRAF mutation. Taken together, these finding suggest that PTC is not the predominant precursor of ATCs. The limitation of this part of study is that RET/PTC chimeric gene was not examined because analyzing the fusion gene requires tumor RNA while our specimens were archive paraffin blocks. Nevertheless, lack of this datum prob-
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FIG. 3. (A) Sequence chromatogram of TP53 shows a change from A to G at nucleotide 13318. (B) Gel electrophoresis of the TP53 RT-PCR products using primer pairs encompassing the 3¢ splice junction of intron 5 showed alternative spliced products (lane 3) as opposed to the normal splicing products (lanes 1 and 2). M, molecular weight marker. B1, normally spliced product of exons 5 and 6; B2, alternatively spliced product containing part of exons 5 and 6 with the entire intron 5; B3, heteroduplex of B1 and B2.
FIG. 2. (A) Sequence chromatogram of BRAF exon 15 encompassing codon 600 shows a heterozygosity (arrow) composed of an altered nucleotide ‘‘A’’ and a wild-type nucleotide ‘‘T,’’ resulting in V600E mutation. (B) An apparent homozygosity of G fi A in PIK3CA exon 9 as pointed by an arrow in the sequence chromatogram will result in E545K mutation. (C) Sequence chromatogram of N-RAS at codon 61 indicated by an arrow shows A fi G (Q61R).
ably would not significantly influence our interpretation because this series comprises only elder patients and it is known that BRAF mutation is the most common genetic alteration in sporadic PTCs of adult patients.5,17 In contrast, RET/PTC chimeric gene is primary found in pediatric PTCs,7,18 particularly those with a history of exposure to external radiation during childhood8 or to ionizing radiation after environmental disasters.6,9,19 Mutated N-RAS was found in approximately onethird of ATCs in our series, and all of them were at codon 61 of N-RAS. This result suggests that ATCs are probably arising from FTCs rather than PTCs because the RAS mutation identified in classical PTCs usually occurs at the codon 12 of K-RAS, whereas that of FTCs is often at the codon 61 of H- or N-RAS.18 Recently, Adeniran et al.13 and Di Cristofaro et al.20 reported a high mutation rate of RAS in FVPTC,
which were all at the codon 61 of RAS. Therefore, it is possible that FVPTC is also a precursor of ATC. The association between FTC/FVPTC and ATC via RAS mutation supports the observation that RAS-positive thyroid carcinomas have a poorer prognosis than those without.21 Reviewing the reported data that analyzed at least 10 cases of ATC, we found that the BRAF mutation rate in ATCs ranged from 6–50% and N-RAS from 7–31% (Table 3). Acknowledging the facts that BRAF mutation is the most common oncogenic defects in PTC and PTC is the most common type of WDC, the reported mutation rates of RAS and BRAF in ATCs suggest that the transformation into ATCs occurs more often in the RASmutated than the BRAF-mutated WDCs. Epidemiologic studies showed that both FTCs and FVPTCs are more common in areas of iodine deficiency than iodine-sufficient areas,38,39 whereas classical PTC is the most frequent type of thyroid cancer in areas of an iodine-rich diet.40,41 These observations suggest that mutation affecting RAS vs BRAF in follicular epithelial cells is, in part, influenced by environmental factors. Although both BRAF and RAS proteins locate in the same signaling pathway, it is intriguing that they lead to different subtypes of WDC. There is no good explanation for this genoAnn. Surg. Oncol. Vol. 14, No. 10, 2007
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TABLE 3. Summary of reported mutations in anaplastic carcinoma of the thyroid Mutation Case numbers (tissue + cell line) 70 50 29 29 20 16 16 10 8 8 8 7 7 7 6 5 5 4 2 2 1 1
(17 + 3) (15 + 1)
(6 + 2) (6 + 1) (0 + 5)
BRAF n (%)
N-RAS n (%)
TP53 n (%)
PIK3CA n (%)
Country
6 (9%) 14 (29%) – 3 (10%) 7 (35%) 8 (50%) 1 (6%) 2 (20%) 5 (63%) – – 0 (0%) – – 2 (33%) – 4 (80%) – 0 (0%) 0 (0%) – 0 (0%)
5 4 4 – – – 5 – 0 3 – 2 – – – – – – – – 1 –
– – – – – – 9 – – – 6 – 5 6 – 1 – 0 – – – –
16 (23%) 6 (12%) – – – – 0 (0%) – – – – – – – – – – – – – – –
Spain and Italy14 USA22 Spain and USA21 Italy and USA23 Brazil, Portugal, and Spain24 USA25 Taiwan (This study) USA26 USA27 Italy28 USA15 Japan29 Italy30 Japan31 Japan7 Saudi Arabia32 USA8 Taiwan33 Italy34 Taiwan35 UK36 Italy37
(7%) (8%) (14%)
(31%) (0%) (38%) (29%)
(100%)
type-phenotype relationship. However, it is possible that the connection between the upstream RAS and other signal transducers causes additional oncogenic effects that are not achievable by the downstream BRAF-activated signaling. In this regard, it is known that GTP-loaded RAS binds and interacts with the catalytic subunit of PI3K, which is encoded by PIK3CA.42 From this perspective, it is interesting that PIK3CA mutation was recently reported in ATCs.14,22 Unfortunately, we were not able to confirm this finding because PIK3CA mutation was detected in PTC rather than in the coexisted ATC (case No. 8). In this study, we found 56% of ATCs had TP53 mutation, confirming the long-standing observation that TP53 mutation is one of the most common genetic alterations found in human cancers including ATCs (Table 3). As to the three tumors (cases No. 8, 10, and 13) that contained both ATCs and PTCs, we found TP53 mutation in ATCs but not in PTC components, supporting the long-held theory that TP53 mutation represents a late genetic event in thyroid carcinogenesis.30 In most human cancers, TP53 mutations are predominantly point mutations and rarely splicing mutations, which account for less than 2% of the database.43 Interestingly, we detected a novel mutation IVS5-2A>G involving the splice acceptor (SA) of intron 5. The RT-PCR showed the presence of an alternatively spliced product, suggesting that it is a Ann. Surg. Oncol. Vol. 14, No. 10, 2007
(56%)
(75%) (71%) (86%) (20%) (0%)
splicing mutation. Although this mutation has not been reported in the literature, a similar splicing mutation affecting intron 5 SA, IVS5-1G>A, was reported in Li-Fraumeni syndrome.43 In that study, Varley et al. showed that intron 5 SA mutation increased the cell survival following low-dose rate irradiation. In conclusion, our result showed that approximately 31% of ATCs had N-RAS mutation and 6% harbored BRAF mutation. As FTCs and FVPTCs are known to account for the majority of WDC that have RAS mutation, our result suggests that these two types of WDC are probably the major precursor of the ATC that do not occur de novo. Acknowledging that ATC is an aggressive cancer with a dismal prognosis, our finding therefore emphasizes the importance of close follow-up in patients with RASmutated WDC. ACKNOWLEDGMENT This study was supported in part by grants from National Science Council (NSC95-2320-B-195-001).
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