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Original Studies |
Departments of Pathology and Laboratory Medicine, Surgery, Medicine, and Otolaryngology, Mount Sinai Hospital and the University of Toronto, Toronto, Ontario, Canada M5G 1X5
Address all correspondence and requests for reprints to: Sylvia L. Asa, M.D., Ph.D., Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5 Canada. E-mail: sasa{at}mtsinai.on.ca
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A wide range of prevalence of RET/PTC rearrangements in human sporadic PC, from 5–44% (4), has been attributed to differing methodology and/or geographic factors (4, 5, 6). A 67–87% prevalence of RET/PTC rearrangements has been reported in pediatric thyroid carcinoma associated with radiation exposure from the Chernobyl nuclear accident (7, 8) with unusual predominance of the RET/PTC-3 form (8). There is a high (48–65%) prevalence of the rearrangement in childhood thyroid carcinoma, in general (8, 9).
The clinical significance of RET/PTC is uncertain. One group has postulated its importance in the development of distant metastatic disease (10). To correlate the presence of RET/PTC rearrangements with histologic and clinical prognostic features, we previously examined a series of 60 thyroid carcinomas and found that rearrangements are rare but are associated with lymphatic involvement in otherwise low-risk patients of young age with small tumors (4). Another group had similar findings (11). In contrast to these data, however, a recent paper reported a 42% prevalence of RET/PTC rearrangements in occult papillary thyroid microcarcinomas (12). This intriguing report, showing such high prevalence in small, clinically occult tumors, did not directly compare those lesions with clinically evident tumors, however, and the number of patients studied was small.
In this study, we investigated RET/PTC rearrangements in clinically manifest and clinically occult papillary carcinomas and in patients with multifocal papillary carcinoma of both types to address the following questions: 1) Are RET/PTC rearrangements early events in thyroid tumorigenesis? 2) Are RET/PTC rearrangements associated with progression to clinically manifest PC? 3) Do individual foci of tumor in patients with multifocal disease contain the same or different RET/PTC rearrangements?
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Materials and Methods |
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Tissue blocks were retrieved from thyroidectomy specimens of 21 patients with papillary thyroid microcarcinomas obtained from the pathology files of Mount Sinai Hospital between 1993 and 1997. Thirteen thyroids had occult tumors only, and 9 of these had multiple microcarcinomas; 8 had clinically manifest PCs and at least one separate focus of occult papillary microcarcinoma.
To validate the results obtained from formalin-fixed, paraffin-embedded tissues, we examined RNA from paraffin and corresponding tumor RNA extracted from snap-frozen tissues from 36 patients with clinically evident PC from the same time period.
Histology
Tissues fixed in neutral buffered formalin were totally embedded in paraffin in 3- to 4-mm blocks, and 5-micron-thick sections were stained with hematoxylin and eosin for histologic examination (13). Papillary carcinomas were identified by nuclear and architectural features (14) and, if necessary, were confirmed by immunohistochemistry (IHC) for high-molecular-weight cytokeratins (15).
Paraffin blocks containing tumor were sectioned to obtain tissue for RNA extraction and immunohistochemical evaluation of RET expression. Because of the small size of the occult tumors, blocks were cut in the following sequence to confirm the presence of tumor in extracted RNA: 1) a 20-micron section was cut first for RNA extraction; and 2) a 5-micron section was then cut for immunohistochemical analysis and confirmation of tumor continuity. The microtome blade was cleaned between samples to prevent contamination from one specimen to the next.
RNA extraction
Tissue sections, 20-micron thick, were deparaffinized in 1 mL xylene at room temperature for 20 min and washed once with 100% ethanol. After centrifugation, the pellet was air dried and resuspended in 200 µL of solution containing 6 mg/mL proteinase K (Sigma Canada Ltd, Oakville, Ontario), 1 mol/L guanidinium isocyanate, 25 mmol/L ß-mercaptoethanol, 0.5% Sarcosyl, and 20 mmol/L Tris (pH 7.5) and was incubated at 45 C for 6 h with agitation. One equivalent volume of 70% phenol/30% chloroform was added for precipitation at 4 C for 20 min, followed by centrifugation at 14,000 x g. Overnight precipitation at -20 C followed addition of 1 vol isopropanol and 2 µg glycogen to the aqueous supernatant. The pellet formed after centrifugation at 14,000 x g was washed with 70% ethanol, air dried, and resuspended in 10 µL diethyl pyrocarbonate water containing ribonuclease inhibitor.
RNA was extracted from frozen tissue of clinically evident tumors, as previously described (4).
RT-PCR
RT was performed on one-fifth of the paraffin-extracted RNA sample. The reaction mixture contained 5 mmol/L MgCl2, 1 mmol/L deoxynucleotide triphosphate, 2.5 µmol/L respective antisense primer, 1 U/µL ribonuclease inhibitor, and 0.125 U/µL Maloney leukemia virus reverse transcriptase (Perkin-Elmer Corp., Branchburg, NJ) in a total vol of 10 µL. RT was performed in a Perkin-Elmer, Corp. 9600 PCR machine for 15 min at 42 C, followed by 5 min of denaturation at 99 C, and cooled for 5 min at 5 C. The integrity of the RNA and efficiency of the RT reaction in each sample was confirmed by PCR for the housekeeping gene PGK-1 (4). Each reaction mixture contained a total concentration of 1 µmol/L sense and 1 µmol/L antisense primers (0.5 µmol/L from RT reaction and 0.5 µmol/L added primers), 0.3 mmol/L deoxynucleotide triphosphates, 2 mmol/L MgCl2, and 5 U/µL Taq polymerase (Perkin-Elmer Corp., Branchburg, NJ). The primer positions are: 5' 188–208, 3' 372–392 for RET/PTC-1 (16), 5' 605–625, 3' 768–788 for RET/PTC-2 (17), and 5' 612–632, 3' 919–939 for RET/PTC-3 (18). After initial denaturation at 94 C for 2 min, amplification was performed over 35 cycles consisting of 94 C for 30 sec, 57 C (PGK-1) or 55 C for 2 min (RET/PTC-1, -2, and -3), 72 C for 2 min, and a final extension at 72 C for 4 min. Negative controls performed with each RT-PCR reaction omitted either template or reverse transcriptase. The products were resolved on a 1.2% agarose gel containing ethidium bromide and were visualized under ultraviolet light.
Samples exhibiting RET immunoreactivity, but no RET/PTC rearrangement by RT-PCR, were subsequently examined for expression of the cytoplasmic portion of RET by RT-PCR, as previously described (8).
Southern hybridization
PCR products were transferred to nylon membranes (Boehringer-Mannheim, Laval, Quebec) by upward capillary action in 20 x saline-sodium citrate followed by ultraviolet cross-linking. Digoxigenin-labeled probes were generated by PCR reactions or random priming using complementary DNA generated from thyroid tumors positive for RET/PTC-1 and -3 (4) as templates. The RET/PTC-2 complementary DNA template was kindly provided by S. Jhiang (Columbus, Ohio). The primers for each probe were identical to those used for RT-PCR (4). Labeling, hybridization, and detection were performed according to manufacturer’s protocol (Boehringer-Mannheim).
IHC
Immunostaining used a rabbit polyclonal IgG antibody to the carboxyterminus of RET (Santa Cruz Biotechnology, Inc., Santa Cruz, CA); negative controls replaced primary antiserum with nonimmune rabbit serum. Tissue sections, 5-micron thick, were pretreated with 45% formic acid for 15 min at room temperature. After blocking endogenous peroxidase and nonspecific binding, the primary antibody, at a dilution of 1:1000, was incubated at room temperature overnight, followed by detection with the ultrastreptavidin system (Signet, Dedham, MA).
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Results |
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Thirty-nine papillary thyroid microcarcinomas of 21 patients
measured from 1–8 mm, with an average size of 2.3 mm. None of the
tumors had rearrangements detected by ethidium bromide staining of
RT-PCR products. RNA integrity was confirmed with RT-PCR of PGK-1, a
housekeeping gene. Southern hybridization, using digoxigenin-labeled
probes, revealed that 30 (77%) of the 39 occult tumors were positive
for RET/PTC rearrangements. Of the 30 tumors, 12 were
positive for RET/PTC-1, 3 for RET/PTC-2, and 6
for RET/PTC-3 (Fig. 1
). There
were 9 tumors positive for multiple RET/PTC oncogenes (Table 1). Omission of reverse transcriptase or
replacing template with water yielded no product (Fig. 2). Nontumorous thyroid tissue from 16 of
the 21 patients included 3 positive samples; thyroiditis was present in
2 of these.
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); 5 tumors were
excluded because of artifacts on tissue sections. The staining was
cytoplasmic, consistent with loss of the transmembrane domain of
RET during rearrangement. Positivity was focal in some
tumors. Normal thyroid epithelial cells did not demonstrate staining.
However, there was staining seen in macrophages, particularly in
samples containing moderate to severe thyroiditis.
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RET rearrangements are more frequent in occult, compared with clinically evident papillary neoplasms
Eight patients had clinically evident papillary carcinoma and at
least one occult microcarcinoma. In this group, 5 of 9 clinically
evident PCs had RET/PTC rearrangements (Table
2).
The high frequency of detection of RET/PTC rearrangements in
RNA extracted from paraffin was unexpected and may have reflected an
artifact of the technical procedure. We therefore performed RT-PCR and
Southern hybridization on tumor RNA obtained from snap-frozen tissue of
clinically evident tumors during a previous study (4). Thirty-six of
the original 57 samples were available. Three of the 36 samples had
RET/PTC rearrangements previously detected with ethidium
bromide staining alone; however, with Southern hybridization, the
detection of RET/PTC oncogenes increased to 16 (44%) (Fig. 4). Among these, 8 were positive for
RET/PTC-1, 2 for RET/PTC-2, and 4 for
RET/PTC-3; 2 tumors were positive for multiple
RET/PTC oncogenes. Moreover, RT-PCR of RNA extracted from
the paraffin-embedded tissue corresponding to these frozen samples
confirmed the results, proving that the higher incidence is not caused
by an artifact of tissue processing. Instead, the sensitivity of
Southern hybridization accounts for the higher incidence of detection.
IHC also confirmed immunoreactivity for RET in these tumors
(Fig. 3b).
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2 test). In
both occult and clinically evident PC, the most frequent rearrangement
is RET/PTC-1, followed by -3 and then -2 (Table 1, Fig. 5).
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We further analyzed our data to examine the diversity of
RET/PTC expression in multifocal PC. There were 17 who had
multifocal disease. Nine patients had undergone thyroidectomy for
nodular hyperplasia, and 8 patients had clinically evident tumor
nodules. Thirty-two of 44 tumors, including occult and clinically
evident lesions, expressed RET/PTC (Tables 2 and 3); RET/PTC-1 was found in 12
tumors, RET/PTC-2 in 3, RET/PTC-3 in 6, and
multiple rearrangements in 11. Two of the 17 patients (Table 2,
patients C and G) had either no RET/PTC rearrangements or
identical RET/PTC rearrangements within their multiple
tumors, and 15 of the 17 patients had diverse rearrangements (Tables 2 and 3). In the 8 patients who had associated clinical tumors,
RET/PTC rearrangements were detected in 5 of 9 clinically
evident tumors and in all 11 occult tumors. One patient (Table 2,
patient L) had cervical lymph node metastases, and both metastases
analyzed had rearrangements. Interestingly, one lymph node had the same
rearrangement (RET/PTC-1) as the dominant tumor nodule,
whereas the other lymph node had the same rearrangement
(RET/PTC-2) as an occult tumor nodule, which measured only
0.8 cm in size (Table 2, patient L).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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or the TSH receptor have been reported in
functional follicular adenomas (21, 22). Overexpression of
c-met and trk rearrangements are found in PC (23, 24). Mutations of p53 are late events, restricted to anaplastic
carcinomas (25); however, accumulation of p53 protein is predictive of
poor clinical outcome in patients with differentiated thyroid carcinoma
(26, 27).
The RET/PTC oncogene is unique to PC (28). It is composed of
several rearranged forms of the RET protooncogene, a
transmembrane tyrosine kinase receptor. The rearrangements result in
constitutive tyrosine kinase activation and translocation of the fusion
protein to the cytoplasm (29). There have been five rearrangements
described, each transposing a cellular gene adjacent to the tyrosine
kinase domain of RET (RET TK). Paracentric
inversions of chromosome 10 result in juxtaposition of the cellular
genes H4 (RET/PTC-1) or ele1 (RET/PTC-3, -4)
adjacent to RET TK (30, 31, 32, 33). Rearrangement with chromosome
17 forms RET/PTC-2, transposing the RI subunit of
cAMP-dependent protein kinase A adjacent to the RET TK (34).
RET/PTC-5 was recently found in PCs from two patients
exposed to radiation from the Chernobyl accident (35).
PCs exhibit a wide range of biological behavior. Occult papillary thyroid microcarcinomas, defined as smaller than 1 cm and clinically nonpalpable, have been identified as incidental findings; however, they are also frequently associated with clinically detected papillary carcinoma and, in that setting, they have been attributed to lymphatic dissemination (14). In patients without clinical carcinoma, the high (30%) incidence in autopsy series (36) and in thyroids surgically resected for benign disease (13) suggests that most of these tumors remain quiescent and are clinically insignificant. Our results demonstrate that RET/PTC rearrangements are highly prevalent (77%) in occult papillary thyroid microcarcinomas. Viglietto et al. (12) found RET/PTC-1 rearrangements in 11 of 26 (42%) occult microcarcinomas using similar methodology. In our samples, the distribution of RET/PTC subtypes is similar to previous reports in sporadic PC, with RET/PTC-1 being the most common, followed by RET/PTC-3 and then RET/PTC-2. RET/PTC-4, which would have been detected with the primers for RET/PTC-3, was not identified in our series.
Interestingly, 9 of 39 occult and 2 clinically detected tumors had 2 forms of RET/PTC. It is difficult to explain this phenomenon if we assume that each tumor arose from an individual transformed cell, although others have reported similar results (37). A precedent for this phenomenon has been found in medullary thyroid carcinomas where subpopulations of tumor have been described with heterogeneous RET mutations (38). One possibility is that normal thyrocytes, subjected to the same genetic or environmental influences, concurrently express different forms of RET/PTC. Normal thyroid tissue has not been demonstrated to have RET/PTC rearrangements, though the detection methods used previously are not as sensitive as RT-PCR with hybridization. With this technique, we found that 3 of 16 corresponding thyroids with no histologic evidence of carcinoma had RET/PTC rearrangements. Two samples had thyroiditis that could have obscured tiny occult tumors. A recent report demonstrated a 95% prevalence of RET rearrangements in patients with Hashimoto’s disease (37). Perhaps the inflammation associated with Hashimoto’s thyroiditis promotes RET rearrangements, leading to the increased risk of papillary thyroid cancer observed in these patients (39).
We wondered whether the unexpectedly high prevalence of rearrangements in occult tumors might be caused by addition of Southern hybridization, which was required for the small samples obtained from paraffin-embedded tissue, a method also used in Viglietto’s study of occult tumors (12). We therefore reexamined samples from a previously reported series of clinically evident papillary thyroid tumors (4). There was a 5-fold increase in detection by hybridization, compared with ethidium bromide detection alone; this was confirmed, in both paraffin-embedded and frozen tissues, to validate the use of paraffin tissue only in the microcarcinomas. The results indicate that there are highly variable levels of RET/PTC expression. The clinical significance of variable levels of RET/PTC RNA is not known. We and others found that abundant RET/PTC expression, detectable with ethidium bromide staining alone, is found in tumors of patients with low-risk clinical parameters and lymphatic involvement (4, 11). In contrast, there was no correlation between clinical parameters and RET/PTC rearrangements expressed at lower levels.
The presence of RET rearrangements in occult tumors (12) and results of in vitro gene transfer studies of RET/PTC in normal follicular cells (40) support the concept that it is an early event in the development of PC. In our study, RET/PTC rearrangements were significantly more common in occult (77%) than clinically evident (47%) PCs using the same methodology, which supports the importance of RET rearrangement early in the development of PC. However, these results also indicate that although RET rearrangement may be sufficient for transformation, it is not required for growth into clinically evident tumors. If we postulate that all clinically evident papillary carcinomas develop from occult tumors, then either occult tumors containing rearranged RET may have a decreased propensity to progress to clinically evident tumors, or loss of RET/PTC in large tumors must occur in a significant proportion.
Our data also address a controversy regarding the significance of multifocal PC: Do these tumors arise independently or are they intraglandular metastases of a single tumor (14)? The answer to this question could have therapeutic implications. Those who support the theory of intraglandular metastases of a single tumor suggest that they indicate an aggressive lesion that warrants further treatment; in contrast, tumors arising independently may simply reflect the propensity of the gland to develop occult tumors, which may or may not progress to clinically significant disease. In multifocal breast (41), prostate (42), and uroepithelial (43) carcinoma, different tumor sites exhibit variable cytogenetic features, LOH or p53 mutations; this has been interpreted as evidence of independent multifocal tumorigenesis (41). Our results indicate that the majority of multifocal thyroid carcinomas have different profiles of RET/PTC, suggesting independent origin. The few multifocal tumors with identical RET/PTC profiles may be the result of intrathyroidal spread of a single tumor, or alternatively, may have arisen independently with identical profiles merely by chance.
In summary, we have identified RET/PTC rearrangements in the majority of occult papillary microcarcinomas, implying a significant role in the initiation of PC. In contrast, rearrangements are present in a lower percentage of clinically manifest tumors. This discrepancy may indicate a decrease in the ability of occult tumors bearing RET/PTC rearrangements to progress to larger tumors. Alternatively, loss of this putative oncogene may be a requirement for progression; this possibility raises questions about the validity of a multistep model of progression of thyroid carcinoma. In multifocal disease, the diversity of RET/PTC profiles in the majority of cases suggests that individual tumors arise independently in a background of genetic or environmental susceptibility.
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Acknowledgments |
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Footnotes |
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2 Current address: The University of Chicago, Department of Surgery,
5841 South Maryland Avenue, MC5031, Chicago, Illinois 60637
Received June 15, 1998.
Revised July 23, 1998.
Accepted July 29, 1998.
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M. L. C. Khoo, N. J. P. Beasley, S. Ezzat, J. L. Freeman, and S. L. Asa Overexpression of Cyclin D1 and Underexpression of p27 Predict Lymph Node Metastases in Papillary Thyroid Carcinoma J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1814 - 1818. [Abstract] [Full Text] [PDF]
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 G. Belchetz, C. C. Cheung, J. Freeman, I. B. Rosen, I. J. Witterick, and S. L. Asa Hurthle Cell Tumors: Using Molecular Techniques to Define a Novel Classification System Arch Otolaryngol Head Neck Surg, March 1, 2002; 128(3): 237 - 240. [Abstract] [Full Text] [PDF]
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M. L. C. Khoo, J. L. Freeman, I. J. Witterick, J. C. Irish, L. E. Rotstein, P. J. Gullane, and S. L. Asa Underexpression of p27/Kip in Thyroid Papillary Microcarcinomas With Gross Metastatic Disease Arch Otolaryngol Head Neck Surg, March 1, 2002; 128(3): 253 - 257. [Abstract] [Full Text] [PDF]
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M. Santoro, M. Papotti, G. Chiappetta, G. Garcia-Rostan, M. Volante, C. Johnson, R. L. Camp, F. Pentimalli, C. Monaco, A. Herrero, et al. RET Activation and Clinicopathologic Features in Poorly Differentiated Thyroid Tumors J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 370 - 379. [Abstract] [Full Text] [PDF]
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R. Elisei, C. Romei, T. Vorontsova, B. Cosci, V. Veremeychik, E. Kuchinskaya, F. Basolo, E. P. Demidchik, P. Miccoli, A. Pinchera, et al. RET/PTC Rearrangements in Thyroid Nodules: Studies in Irradiated and Not Irradiated, Malignant and Benign Thyroid Lesions in Children and Adults J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3211 - 3216. [Abstract] [Full Text] [PDF]
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K M Ropponen, J K Kellokoski, R T Pirinen, K I Moisio, M J Eskelinen, E M Alhava, and V-M Kosma Expression of transcription factor AP-2 in colorectal adenomas and adenocarcinomas; comparison of immunohistochemistry and in situ hybridisation J. Clin. Pathol., July 1, 2001; 54(7): 533 - 538. [Abstract] [Full Text] [PDF]
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C. C. Cheung, B. Carydis, S. Ezzat, Y. C. Bedard, and S. L. Asa Analysis of ret/PTC Gene Rearrangements Refines the Fine Needle Aspiration Diagnosis of Thyroid Cancer J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2187 - 2190. [Abstract] [Full Text]
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E. L. Mazzaferri and R. T. Kloos Current Approaches to Primary Therapy for Papillary and Follicular Thyroid Cancer J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1447 - 1463. [Full Text]
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E. L. Chua, W. M. Wu, K. T. Tran, S. W. McCarthy, C. S. Lauer, D. Dubourdieu, N. Packham, C. J. O’Brien, J. R. Turtle, and Q. Dong Prevalence and Distribution of ret/ptc 1, 2, and 3 in Papillary Thyroid Carcinoma in New Caledonia and Australia J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2733 - 2739. [Abstract] [Full Text]
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C. L. Fenton, Y. Lukes, D. Nicholson, C. A. Dinauer, G. L. Francis, and R. M. Tuttle The ret/PTC Mutations Are Common in Sporadic Papillary Thyroid Carcinoma of Children and Young Adults J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1170 - 1175. [Abstract] [Full Text]
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C. C. Cheung, S. Ezzat, L. Ramyar, J. L. Freeman, and S. L. Asa Molecular Basis of Hurthle Cell Papillary Thyroid Carcinoma J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 878 - 882. [Abstract] [Full Text]
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G. A. Thomas, H. Bunnell, H. A. Cook, E. D. Williams, A. Nerovnya, E. D. Cherstvoy, N. D. Tronko, T. I. Bogdanova, G. Chiappetta, G. Viglietto, et al. High Prevalence of RET/PTC Rearrangements in Ukrainian and Belarussian Post-Chernobyl Thyroid Papillary Carcinomas: A Strong Correlation between RET/PTC3 and the Solid-Follicular Variant J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4232 - 4238. [Abstract] [Full Text]
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C. Soravia, S. L. Sugg, T. Berk, A. Mitri, H. Cheng, S. Gallinger, Z. Cohen, S. L. Asa, and B. V. Bapat Familial Adenomatous Polyposis-Associated Thyroid Cancer : A Clinical, Pathological, and Molecular Genetics Study Am. J. Pathol., January 1, 1999; 154(1): 127 - 135. [Abstract] [Full Text] [PDF]
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