0021-972X/98/$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1998 by The Endocrine Society
Vol. 83, No. 6 Printed in U.S.A.
Polymerase Chain Reaction-Based Microsatellite Polymorphism Analysis of Follicular and Hu ¨ rthle Cell Neoplasms of the Thyroid* DORRY L. SEGEV, MOTOYASU SAJI, GRACE S. PHILLIPS, WILLIAM H. WESTRA, YUMI TAKIYAMA, STEVEN PIANTADOSI, ROBERT C. SMALLRIDGE†, RONALD H. NISHIYAMA, ROBERT UDELSMAN, AND MARTHA A. ZEIGER Department of Surgery, Division of Endocrine and Oncologic Surgery (D.L.S., M.S., G.P., Y.T., R.U., M.A.Z.), Departments of Pathology (W.H.W.) and Biostatistics (S.P.), the Johns Hopkins Medical Institutions, Baltimore, Maryland 21287; and Department of Medicine, Walter Reed Army Medical Center (R.C.S.), Washington, D.C. 20307; and Department of Pathology, Maine Medical Center (R.H.N.), Portland, Maine 04102 ABSTRACT Follicular and Hu¨rthle cell carcinomas of the thyroid cannot be differentiated from adenomas by either preoperative fine needle aspiration or intraoperative frozen section examination, and yet there exist potentially significant differences in the recommended surgical management. We examined, by PCR-based microsatellite polymorphism analysis, DNA obtained from 83 thyroid neoplasms [22 follicular adenomas, 29 follicular carcinomas, 20 Hu¨rthle cell adenomas (HA), and 12 Hu¨rthle cell carcinomas (HC)] to determine whether a pattern of allelic alteration exists that could help distinguish benign from malignant lesions. Alterations were found in only 7.5% of informative PCR reactions from follicular neoplasms, whereas they were found in 23.3% of reactions from Hu¨rthle cell neoplasms. Although there were no significant differences between follicular adenoma and follicular carcinoma, HC demonstrated a significantly
A
PPROXIMATELY half the population in the United States will develop a thyroid nodule by age 65 yr (1). Fine needle aspiration (FNA) cytology is the most accurate diagnostic test in the evaluation of these nodules (2, 3). However, FNA cannot distinguish benign from malignant follicular or Hu¨rthle cell neoplasms (4 –7). Furthermore, intraoperative frozen section evaluation rarely yields additional useful information for the differential diagnosis of these neoplasms (8). The diagnosis of carcinoma requires the histological documentation on permanent section of tumor invasion, either into blood vessels or beyond the tumor capsule. In many cases, tumor invasion is a focal finding and apparent only upon careful analysis of multiple histological sections (9). Complicating this clinical dilemma, optimal surgical
Received September 15, 1997. Revision received January 12, 1998. Accepted March 3, 1998. Address all correspondence and requests for reprints to: Dr. Martha A. Zeiger, 600 N. Wolfe Street, Carnegie 681, Department of Surgery, Division of Endocrine and Oncologic Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-8611. E-mail:
[email protected]. * This work was supported by the Interthyr Research Foundation (to M.S.), the Johns Hopkins Oncology Center, and a NIH OPD-GCRC CAP award (to M.A.Z.). † Current address: Division of Endocrinology, Mayo Clinic Jacksonville, Jacksonville, Florida 32224.
greater percentage of allelic alteration than HA on chromosomal arms 1q (P , 0.001) and 2p (P , 0.05) by Fisher’s exact test. The documentation of an alteration on either 1q or 2p was 100% sensitive and 65% specific in the detection of HC (P , 0.0005, by McNemar’s test). In conclusion, PCR-based microsatellite polymorphism analysis may be a useful technique in distinguishing HC from HA. Potentially, the application of this technique to aspirated material may allow this distinction preoperatively and thus facilitate more optimal surgical management. Consistent regions of allelic alteration may also indicate the locations of critical genes, such as tumor suppressor genes or oncogenes, that are important in the progression from adenoma to carcinoma. Finally, this study demonstrates that Hu¨rthle cell neoplasms, now considered variants of follicular neoplasms, differ significantly from follicular neoplasms on a molecular level. (J Clin Endocrinol Metab 83: 2036 –2042, 1998)
management of adenomas vs. carcinomas differs significantly; adenomas can be treated with lobectomy, whereas patients with carcinoma may benefit from total thyroidectomy (1, 10). As a definitive diagnosis can rarely be made either pre- or intraoperatively, patients with adenomas may undergo surgery that is more extensive than necessary, and conversely, patients with carcinomas may receive less than adequate surgery. Recent studies have demonstrated that thyroid carcinomas may result from a series of defined genetic alterations (11). In terms of the distinction between follicular or Hu¨rthle cell adenomas from carcinomas, others have examined these tumors by cytogenetic studies, loss of heterozygosity studies with restriction fragment length polymorphisms (12–14), as well as examination for mutations or overexpression of tumor suppressor genes and oncogenes, respectively (15, 16). We have previously demonstrated that measurement of telomerase activity can distinguish follicular carcinoma (FC) from follicular adenoma (FA) with 100% sensitivity and 76% specificity (17). Despite these studies, however, there is no other genetic abnormality that can reliably distinguish benign from malignant follicular or Hu¨rthle cell neoplasms. PCR-based microsatellite analysis is a more sensitive method than restriction fragment length polymorphism
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ALLELOTYPING OF THYROID NEOPLASMS
2037
analysis for detecting chromosomal abnormalities (18, 19). In fact, allelotype analysis is now available for most tumor types and has been used in the evaluation of head and neck (20), renal (21), and colorectal (22) carcinomas. Zedenius et al. recently examined allelotypes of both follicular and Hu¨rthle cell neoplasms by this method and demonstrated that 10q may be involved in follicular thyroid tumor progression and that the majority of Hu¨rthle cell adenomas (HA) showed abnormalities on 3q or 18q (23, 24). Aberrations on chromosomal arms 3p and 11q have also been implicated by others in the progression of follicular neoplasms (12, 13, 25). We therefore examined allelotypes in 83 thyroid neoplasms [22 FA, 29 FC, 20 HA, and 12 Hu¨rthle cell carcinomas (HC)] in an attempt to elucidate a genetic model of tumor progression and to identify a pattern of allelic alteration that might reliably distinguish benign from malignant neoplasms. We found that there was no difference in allelotyping between FA and FC, but that two chromosomal arms, 1q and 2p, had a significantly greater percentage of alterations in HC than in HA. Materials and Methods Thyroid tissue and DNA extraction Paraffin-embedded or fresh-frozen follicular and Hu¨rthle cell neoplasms and corresponding normal thyroid tissue and/or blood lymphocytes were collected from patients at the Johns Hopkins Medical Institutions, Walter Reed Army Medical Center, and Maine Medical Center. All tumors were primary thyroid tumors. Six to 10 adjacent 5-mm sections were cut from blocks and mounted on glass slides. All original slides stained with hematoxylin and eosin were reviewed to confirm the diagnosis by a single pathologist (W.H.W.). DNA from paraffin-embedded tissue or blood cells was extracted as previously described (26). DNA was extracted from frozen sections after microdissection and treatment with proteinase K followed by phenolchloroform extraction, as described previously (26). Patients were studied under protocol M1011 approved by the Johns Hopkins Joint Committee on Clinical Investigation.
PCR-based microsatellite analysis PCR reactions were performed as previously described (27, 28). Microsatellite primers were obtained from Research Genetics (Huntsville, AL), and their chromosomal locations were confirmed by marker maps obtained from the Cooperative Human Linkage Center worldwide web site.1 One primer from each pair was end labeled with T4 kinase (New England Biolabs, Beverly, MA) and g[32P]ATP (DuPont-New England Nuclear, Boston, MA). PCR reactions were carried out in a total volume of 10 mL containing 5–20 ng genomic DNA, 4 ng labeled primer, and 20 ng unlabeled primer in 35 cycles consisting of denaturing at 94 C for 60 s, annealing at 55– 60 C for 60 s, and extension at 72 C for 120 s. After PCR, 5 mL of the reaction plus 5 mL 80% formamide were separated on a 40% formamide and 8.3 mol/L urea-6% polyacrylamide gel. Gels were dried, and autoradiography was performed with Kodak X-Omat (Eastman Kodak, Rochester, NY) for 4 – 48 h at room temperature or 270 C.
Definition of allelic alterations For informative cases, alterations included allelic loss or gain (20, 23, 27) (Fig. 1). Loss was determined in heterozygous samples by comparing the intensity of the alleles in tumor DNA to that in corresponding normal 1 World-Wide-Web site for Cooperative Human Linkage Center is www.chlc.org. The map used in this report was Sex-Averaged Recombination Minimization Maps of the Genome, Version 4.0, and Version 8.0 Likely Locations of Current CHLC Markers in Version 2.0 skeletal Maps.
FIG. 1. Microsatellite analysis of representative cases. DNA from primary tumor (T) and corresponding normal thyroid or blood cells (N) were isolated and amplified by PCR. Microsatellite markers are designated below each figure: a, HC 9 shows retention of both alleles, and HA 24 and HC 25 show loss of lower allele in T at D1S1665 (1p); b, FA 5 shows retention of both alleles, and HC 9 shows loss of upper allele in T at D2S1326 (2q); and 3) FC 66 shows retention of both alleles, FC 67 shows gain of upper allele, and FC 68 shows loss of lower allele at D3S3038 (3p).
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DNA using densitometry (Molecular Dynamics, Sunnyvale, CA). If the ratio of the two alleles in normal DNA was twice that of the alleles in tumor DNA, it was considered an allelic loss. Gain of an allele was considered to exist if additional bands were noted. Constitutional homozygosity was regarded as noninformative.
sensitive and 65% specific (P , 0.0005) in the detection of HC, with positive and negative predictive values of 63% and 100%, respectively. Discussion
Statistical analysis A tumor was considered positive for allelic alteration on a chromosomal arm if one or more markers demonstrated an alteration. For each marker and each chromosomal arm, the difference between the percent alteration for carcinoma and adenoma, defined as the number demonstrating alterations/number of informative cases, was tested for statistical significance using Fisher’s exact test with P , 0.05. Patterns of alteration on several chromosomal arms were examined by McNemar’s test for correlated proportions (29).
Results
A total of 83 follicular and Hu¨rthle cell neoplasms of the thyroid (Table 1) were examined for allelic alteration by PCR-based microsatellite polymorphism analysis of most chromosomal arms using 65 microsatellite markers (Tables 2 and 3). Among all informative PCR reactions from follicular neoplasms, 7.5% reactions showed alterations (5.8% in FA and 9.1% in FC). In contrast, 20.3% and 27.1% of informative reactions from HA and HC, respectively, displayed alterations (Table 1). There was no correlation between the percentage of allelic alteration and either tumor size or patient age for any group (Table 1). There were no statistically significant differences in allelic alteration seen in FA vs. FC at any of the individual markers tested or on any chromosomal arm (Table 2 and Fig. 2). Although there were also no statistically significant differences between HA and HC at any one marker (Table 3 and Fig. 2), HC did demonstrate statistically significant differences compared to HA on chromosomal arms 1q (92% vs. 30%, P , 0.001) and 2p (50% vs. 12%, P , 0.05) by Fisher’s exact test (Table 3). In all cases the allelic patterns seen in normal thyroid corresponded to those seen in blood lymphocytes (data not shown). Combinations of alterations seen on several markers were examined by McNemar’s test for correlated proportions to determine whether there was a pattern that would reliably distinguish HA from HC. The combination of markers on chromosomal arm 1q (D1S534, D1S518, and D1S549) and that on 2p (D2S1780 and D2S1788) were statistically significantly different (Table 4). For instance, the demonstration of alteration on either 1q or 2p was 100% TABLE 1. Follicular and Hu¨rthle cell neoplasms, number, patient age, tumor size, and percentage of markers with alteration
No. Age (yr) Tumor size (cm) % with alteration
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SEGEV ET AL.
FA
FC
HA
HC
22 33 6 7 2.1 6 1.3 5.8
29 53 6 19 2.4 6 1.5 9.1
20 47 6 14 2.6 6 1.3 20.3
12 55 6 16 2.3 6 1.2 27.1
FA, Follicular adenoma; FC, follicular carcinoma; HA, Hu¨rthle cell adenoma; HC, Hu¨rthle cell carcinoma of the thyroid. Tumor size used was maximum diameter recorded. Percent alteration is expressed as: number reactions demonstrating allelic alteration/number of informative reactions. Patients with FA were significantly younger than patients in other groups, but otherwise there was no significant difference in age among groups.
The exact molecular abnormalities responsible for the progression of normal thyroid tissue to thyroid neoplasia are poorly understood. Most thyroid neoplasms are clonal, arising from a single precursor cell that has acquired one or more mutations, thereby contributing to its uncontrolled growth (30). Although others have reported abnormalities on 3p and 11q in follicular neoplasms, 3q and 18q in Hu¨rthle cell adenomas, and 10q in both FA and HA (14, 23, 24), our data demonstrated infrequent alterations on these chromosomal arms. This discrepancy may result from the fact that different markers were examined. Because both follicular and Hu¨rthle cell neoplasms demonstrate similar architectures on permanent histological section, Hu¨rthle cell neoplasms are considered variants of follicular neoplasms (4, 7, 31). However, clinically, patients with HC have a worse prognosis than patients with FC (7, 31–33). Our results support this clinical difference insofar as we found that Hu¨rthle cell neoplasms have a significantly higher frequency of allelic alteration than follicular neoplasms. Our data also support the idea that Hu¨rthle cell neoplasms differ from follicular neoplasms on a molecular level and may explain their more aggressive behavior. In this study, although we did not demonstrate a difference in allelic alterations between FC and FA, we did show that alterations on 1q and 2p were significantly more frequent in HC than HA. Various oncogenes and tumor suppressor genes have been described on these chromosomal arms (34 – 41), each of which might be involved in the progression from benign to malignant Hu¨rthle cell tumors. Whether the progression from HA to HC involves one or more of these genes or a novel gene might be better understood after more extensive microsatellite mapping studies of the neoplasms on 1q and 2p. Relevant to the clinical dilemma of preoperative differentiation of Hu¨rthle cell neoplasms, the pattern of chromosomal alteration on either 1q or 2p can distinguish HC from HA with 100% sensitivity and 65% specificity. Although our data are derived from frozen and paraffinembedded neoplasms, preliminary work suggests that DNA extracted from corresponding FNA samples correlates with chromosomal alterations demonstrated in the tumors (26). Furthermore, allelic patterns were identical in normal thyroid and blood lymphocytes (data not shown), supporting the plausibility of using PCR-based microsatellite analysis of FNA samples and concomitant blood lymphocytes in the preoperative evaluation of Hu¨rthle cell neoplasms of the thyroid. In conclusion, the pattern of chromosomal alteration documented in this study may be important in further elucidating the genetic mechanisms responsible for thyroid carcinogenesis. The ability to distinguish HA from HC preoperatively also has enormous clinical and economic implications and theoretically may allow for more optimal
ALLELOTYPING OF THYROID NEOPLASMS
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TABLE 2. Summary of microsatellite analysis of follicular neoplasms Chromosomal arm
1p 1q 2p 2q 3p
3q 4p 4q 5p 5q 6p 6q 7p 7q 8p 8q 9p 9q 10p 10q 11p 11q 12p 12q 13p 13q 14q 15q 16p 16q 17p 17q 18p 18q 19p 19q 20p 21q 22q
Marker
D1S1597 D1S1665 D1S534 D1S549 D2S1788 D2S1326 D2S1384 D3S3038 D3S2432 D3S1768 D3S2409 D3S1766 D3S1764 D3S2427 D4S2639 D4S2623 D4S2361 D4S1625 D4S1652 GATA84E11 D5S1456 D6S1017 D6S474 D6S1277 D7S2201 D7S1824 D8S1145 D8S1132 D8S1128 D9S925 D9S301 D9S922 D9S938 D9S158 D10S1426 D10S1237 D11S1392 GATA64D03 D12S391 D12S395 D13S787 D13S317 D13S796 D14S306 D14S606 D14S617 D15S659 D15652 D15S642 D162619 D16S2624 D17S1303 D17S1301 D18S843 D18S858 D18S844 D19S247 D19S714 D19S246 D20S470 D21S1270 D21S1446 D22S685
Follicular adenomas
Follicular carcinomas
A
(%)
T
(%)
0/7 1/12 1/14 1/12 0/8 0/17 1/17 0/11 0/16 0/13 0/12 1/9 2/14 0/13 1/16 0/5 0/9 2/15 0/7 0/8 1/11 2/17 1/15 1/16 0/19 2/13 1/12 1/13 0/15 2/18 1/13 0/5 0/3 0/5 2/15 0/9 3/16 2/13 2/18 0/13 3/15 1/18 1/20 1/12 1/9 1/14 0/18 0/10 0/8 0/19 1/18 1/17 0/12 2/14 0/15 0/8 1/12 0/5 0/14 0/14 0/16 2/16 1/12
(0) (8) (7) (8) (0) (0) (6) (0) (0) (0) (0) (11) (14) (0) (6) (0) (0) (13) (0) (0) (9) (12) (7) (6) (0) (15) (8) (8) (0) (11) (8) (0) (0) (0) (13) (0) (19) (15) (11) (0) (20) (6) (5) (8) (11) (7) (0) (0) (0) (0) (6) (6) (0) (14) (0) (0) (8) (0) (0) (0) (0) (13) (8)
1/17
(6)
2/19
(11)
1/20
(5)
1/20
(5)
2/17
(12)
1/17
(6)
2/18
(11)
2/19
(11)
1/18
(6)
3/20
(15)
0/5
(0)
5/22
(23)
2/18
(11)
0/20
(0)
0/16
(0)
1/13
(8)
2/20
(10)
A
(%)
T
(%)
0/3 3/17 0/6 0/19 1/10 3/22 2/22 2/13 1/23 3/13 0/12 1/7 0/12 2/12 0/13 0/2 0/4 0/19 0/3 2/11 0/10 3/14 3/24 2/21 0/15 0/14 0/18 0/7 2/18 1/15 3/10 0/1 0/3 0/1 2/13 1/8 1/19 3/18 2/23 0/18 4/15 0/17 2/27 1/15 0/7 1/14 0/20 3/12 0/1 1/19 1/21 1/18 2/11 2/12 3/12 0/1 0/3 0/7 1/19 5/20 2/21 0/8 4/19
(0) (18) (0) (0) (10) (14) (9) (15) (4) (23) (0) (14) (0) (17) (0) (0) (0) (0) (0) (18) (0) (21) (13) (10) (0) (0) (0) (0) (11) (7) (30) (0) (0) (0) (15) (13) (5) (17) (9) (0) (27) (0) (7) (7) (0) (7) (0) (25) (0) (5) (5) (6) (18) (17) (25) (0) (0) (0) (5) (25) (10) (0) (21)
3/18
(17)
0/21
(0)
3/25
(12)
6/28
(21)
2/16
(13)
0/13
(0)
0/21
(0)
4/26
(15)
2/20
(10)
4/20
(20)
0/3
(0)
6/29
(21)
2/17
(12)
3/23
(13)
3/13
(23)
0/7
(0)
2/23
(9)
A, Number of tumors demonstrating allelic alteration/number of informative cases; T, number of tumors demonstrating allelic alteration at one or more markers on the chromosomal arm/number of informative cases; %, the resulting percentages calculated.
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SEGEV ET AL.
TABLE 3. Summary of microsatellite analysis of Hu¨rthle cell neoplasms Chromosomal arm
1p 1qa 2pa 2q 3p
3q 4p 4q 5p 5q 6p 6q 7p 7q 8p 8q 9p 9q 10p 10q 11p 11q 12p 12q 13p 13q 14q 15q 16p 16q 17p 17q 18p 18q 19p 19q 20p 21q 22q
Marker
D1S1597 D1S1665 D1S534 D1S518 D1S549 D2S1780 D2S1788 D2S1326 D2S1384 D3S3038 D3S2432 D3S1768 D3S2409 D3S1766 D3S1764 D3S2427 D4S2639 D4S2361 D4S2623 D4S1625 D4S1652 GATA84E11 D5S1456 D6S1017 D6S474 D6S1277 D7S2201 D7S1824 D8S1145 D8S1132 D8S1128 D9S925 D9S301 D9S922 D9S938 D9S158 D10S1426 D10S1237 D11S1392 GATA64D03 D12S391 D12S395 D13S787 D13S317 D13S796 D14S306 D14S606 D14S617 D15S659 D15S652 D15S642 D162619 D16S2624 D17S1303 D17S1301 D18S843 D18S858 D18S844 D19S247 D19S714 D19S246 D20S470 D21S1270 D21S1446 D22S685
Hu¨rthle cell adenomas
Hu¨rthle cell carcinomas
A
(%)
T
(%)
A
(%)
5/10 6/15 4/15 3/16 3/16 5/12 2/17 3/9 4/9 0/3 0/6 0/4 1/10 1/3 0/4 0/4 3/7 1/6 1/4 3/9 1/5 3/15 1/8 2/7 3/9 2/5 0/11 1/11 2/8 1/4 2/6 2/11 5/10 0/1 1/2 0/2 0/9 0/4 3/9 2/10 0/10 2/13 1/4 0/3 0/4 1/6 1/6 1/3 4/10 0/11 0/3 0/5 3/11 2/9 1/7 1/13 2/9 1/3 0/6 0/6 1/11 2/8 1/6 0/5 2/5
(50) (40) (27) (19) (19) (42) (12) (33) (44) (0) (0) (0) (10) (33) (0) (0) (43) (17) (25) (33) (20) (20) (13) (29) (33) (40) (0) (9) (25) (25) (33) (18) (50) (0) (50) (0) (0) (0) (33) (20) (0) (15) (25) (0) (0) (17) (17) (33) (40) (0) (0) (0) (27) (22) (14) (8) (22) (33) (0) (0) (9) (25) (17) (0) (40)
9/19
(47)
6/20
(30)
2/17
(12)
6/11
(55)
2/13
(15)
0/5
(0)
4/10
(40)
4/9
(44)
3/9
(33)
2/8
(25)
6/11
(55)
1/3
(33)
1/6
(17)
2/9
(22)
4/13
(31)
3/11
(27)
0/8
(0)
1/8
(13)
1/8 4/11 6/11 4/9 4/10 3/8 5/10 2/5 2/6 0/3 1/6 0/3 3/7 0/2 0/4 1/5 1/4 2/5 1/2 3/4 0/3 2/8 3/7 1/5 2/4 1/5 1/7 2/7 1/5 2/4 2/5 1/8 2/5 0/1 1/2 0/3 2/6 1/3 1/5 1/6 0/4 2/6 0/4 1/5 1/7 1/4 3/5 0/3 1/5 2/6 0/2 0/5 1/7 2/6 1/5 2/8 1/5 0/3 0/2 0/4 2/7 1/4 1/4 0/3 1/4
(13) (36) (55) (44) (40) (38) (50) (40) (33) (0) (17) (0) (43) (0) (0) (20) (25) (40) (50) (75) (0) (25) (43) (20) (50) (20) (14) (29) (20) (50) (40) (13) (40) (0) (50) (0) (33) (33) (20) (17) (0) (33) (0) (20) (14) (25) (60) (0) (20) (33) (0) (0) (14) (33) (20) (25) (20) (0) (0) (0) (29) (25) (25) (0) (25)
T
(%)
5/11
(45)
11/12
(92)
5/10
(50)
3/6
(50)
3/9
(33)
1/7
(14)
2/6
(40)
4/7
(57)
2/6
(33)
4/6
(67)
3/8
(38)
1/4
(25)
2/8
(25)
4/7
(57)
3/7
(43)
1/6
(17)
0/4
(0)
1/5
(20)
A, Number of tumors demonstrating allelic alteration/number of informative cases; T, number of tumors demonstrating allelic alteration at one or more markers on the chromosomal arm/number of informative cases; %, the resulting percentages calculated. Statistical probability per marker and per chromosomal arm was calculated by Fisher’s exact test. a Significant difference between HA and HC, on chromosomal arms 1q and 2p.
ALLELOTYPING OF THYROID NEOPLASMS
FIG. 2. Allelic alteration in follicular and Hu¨rthle cell adenomas and carcinomas of the thyroid calculated as number of tumors with allelic alteration at one or more markers on the chromosomal arm/number of informative cases. * and **, Statistically significant differences per chromosomal arm by Fisher’s exact test (P , 0.05 and P , 0.001, respectively). TABLE 4. Specificity, sensitivity, and positive and negative predictive value in the detection of HC Sensitivity (%)
Positive predictive value (%)
Negative predictive value (%)
Chromosomal markers and arm
Specificity (%)
1q (D1S534, D1S518, and D1S549) 2p (D2S1780 and D2S1788) 1q or 2pa
70
92
65
93
88
50
71
75
65
100
63
100
HA, Hu¨rthle cell adenoma; HC, Hu¨rthle cell carcinoma. All calculations were performed as follows: specificity 5 100 3 (number of HA with allelic retention/number of HA); sensitivity 5 100 3 (number of HC with allelic alterations/number of HC); positive predictive value 5 100 3 (number of HC with allelic alteration/number of both HA and HC with alteration); negative predictive value 5 100 3 (number of HA with allelic retention/number of both HA and HC with chromosomal retention). Statistical probability was calculated by McNemar’s test. a Significant difference between HA and HC (P , 0.005).
surgical management of the patient harboring a Hu¨rthle cell neoplasm. Acknowledgments We thank Drs. David Sidransky, Joseph Califano, and Michael Johns, Jr. (Department of Otolaryngology, Johns Hopkins University, Baltimore, MD), and Michael Deavers, Maj., M.C., U.S.A. (Department of Surgical Pathology, Walter Reed Army Medical Center, Washington DC) for their generous assistance during this study.
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The Third International Symposium on Paget’s Disease Silverado Country Club and Resort Napa, California November 29 –30, 1998 The symposium, which immediately precedes the combined ASBMR-IBMS meeting in San Francisco, will provide a comprehensive program on the advances made in Paget’s disease research and treatment during the last three years. Topics to be covered include epidemiology, genetics, viral etiology, cell biology, complications, and new directions in therapy. Particular emphasis will be placed on the mechanisms of action of bisphosphonates. The registration fee is $100, which includes tuition, CME credit, and all symposium meals. For information, write The Paget Foundation, 120 Wall Street, Suite 1602, New York, New York 10005; or call: 212-509-5335; fax: 212-509-8492; E-mail:
[email protected].
