Progressive genetic alterations of adenoid cystic carcinoma with high-grade transformation.
During the past decade, a variant of ACC with areas of pleomorphic high-grade carcinoma has been recognized. This phenomenon has been historically described as dedifferentiation and is histologically characterized by pleomorphism, prominent necrosis, high mitotic rate beyond even that of conventional solid patterned ACC, and the loss of the biphasic ductal-myoepithelial differentiation. (12) We have recently reported the largest series of these tumors to date, using the designation ACC with high-grade transformation (ACC-HGT), (13) in recognition of the difficulty in reconciling the term dedifferentiated with current concepts in tumor progression. (14,15) ACC-HGT typically occurs in the sixth decade and most commonly involves the sinonasal mucoserous glands, submandibular glands, and palate, with only one case in the parotid reported to date. (16) Unlike conventional ACC, which has a female predilection, the 26 cases of ACC-HGT reported show a slight male predominance of approximately 1.4:1. This tumor is usually grossly aggressive with extraglandular extension for submandibular sites and bone involvement at sinonasal or palatine sites. The high-grade transformed areas typically present de novo, although there are at least 3 reported cases of transformation on recurrence. (12,17) Histologic patterns of the transformed areas range from a cribriform high-grade adenocarcinoma to solid carcinoma with squamoid features. Micropapillary growth pattern calcifications have been noted reminiscent of salivary duct carcinoma, although the apocrine morphology is lacking and androgen receptor and HER2/neu are typically negative by immunohistochemistry. A key feature of transformed areas is the loss of the biphasic appearance, which can be demonstrated immunohistochemically by the loss of the abluminal myoepithelial layer. (4,12,13,18-20) This variant may be even more aggressive than conventional solid ACC and has a greater capacity for nodal metastasis. Of note, unlike conventional ACC, 1 case of ACC-HGT has recently been shown to respond favorably to a docetaxel-cisplatinradiotherapy regimen, raising the possibility that recognition of high-grade transformation (HGT) may eventually have therapeutic implications. (17)
During the last 2 decades, the molecular pathogenesis of ACC has been enhanced by high throughput gene array analysis identifying several potential biomarkers. (21,22) However, because HGT in these tumors is so rare, very little is known about the underlying genetic events in this phenomenon. Classic biomarkers such as p53 and cyclin D1 are overexpressed by immunohistochemistry, and a small subset of ACC-HGT has been reported to have TP53 mutations. (13,19,20) However, this represents a limited analysis and these alterations are not specific for the phenomenon of dedifferentiation; p53 and cyclin D1 alterations are common even in conventional ACC. (4,23) Identification of genome-wide chromosomal gains or losses in ACC-HGT has not been performed to date. To delineate the chromosomal alterations associated with ACC-HGT we used an array comparative genomic hybridization (aCGH) approach to assess 5 tumors in 4 patients.
MATERIALS AND METHODS Case Selection and Microdissection
This study was performed under a University of Pittsburgh Institutional Review Board approved protocol (IRB#0604184). Five tumors in 4 previously described ACC-HGT with available formalin-fixed paraffin-embedded tissue were selected using histologic criteria as described previously (cases 2, 4, 9, and 10 in previous series (24)). In 1 case, both the primary tumor and metastasis were evaluated. For all cases, the targets consisted of at least 70% transformed component. However, in 2 cases, both the conventional and transformed ACC components were sufficient in both quantity and morphologic distinction to allow for microdissection as 2 separate targets. These targets were microdissected manually from ten to twenty 4-|im unstained histologic sections under direct visualization using a stereoscopic microscope. Genomic DNA was extracted by proteinase K digestion and DNEasy DNA extraction column (Qiagen, Valencia, California). The DNA concentration was quantified using a fluorospectrometer (Nanodrop, Wilmington, Delaware). DNA quality was assured on 2% agarose gel.
Gene gains and losses were detected by commercially available genomic DNA microarray kit GenoSensor Array 300 (Abbott Molecular, Des Plaines, Illinois), which contains triplicates of 287 target clone DNAs (P1 or BAC clones) representing oncogenes and tumor suppressor genes. A complete list of clones can be obtained from www.abbottmolecular.com (last accessed December 1, 2007).
DNA labeling and hybridization were performed according to manufacturer's instructions. Briefly, tumor and reference DNA were labeled by random priming reaction (Random Priming Reaction Kit, Vysis, Downers Grove, Illinois) with Cy3-dCTP and Cy5-dCTP (Perkin Elmer Life Sciences Inc, Boston, Massachusetts), respectively. Labeled tumor and reference DNA were mixed with Microarray Hybridization Buffer (Vysis) containing Cot-1 DNA, followed by denaturation at 80[degrees]C for 10 minutes, followed by a 1-hour incubation at 37[degrees]C. Thirty microliters of hybridization mixture were transferred onto the GenoSensor Array 300-microarray template (Abbott Molecular). Hybridization was carried out for 7 days at 37[degrees]C. Posthybridization washes were performed using washing solution (2XSSC/50% formamide) at 40[degrees]C(3 X 10 minutes), followed by 1XSSC (4 X 5 minutes) and a 1- to 2-second rinse in distilled water. Hybridized DNA was counterstained with DAPI IV solution (Vysis).
The hybridized microarray slides were analyzed using the GenoSencor Reader System (Abbott Molecular). Cy3:Cy5 ratios are automatically determined for each target. The normalized ratios of the test DNA copy number relative to the normal reference DNA copy number is calculated. According to manufacturer's instructions and our own validation using normal DNA versus normal reference DNA, the cut-off fluorescence ratio between normal and aberrant DNA copy numbers was at mean 1.00 plus or minus 2 standard deviations. Fluorescence ratios 1.2 or greater were considered DNA sequence copy number gains, and fluorescence ratios 0.80 or less were considered DNA sequence copy number losses (P < .001).
Fluorescence In Situ Hybridization Validation
Two loci were selected for validation by fluorescence in situ hybridization (FISH) analysis on formalin-fixed paraffin-embedded histologic sections. FISH analysis of C-MYC amplification was performed using standard method with the dual-color LSI CMYC Spectrum Orange/CEP 8 (Spectrum Green) (Vysis). FISH analysis of ERBB2 (formerly HER2/neu) amplification was performed with the dual-color Pathvysion HER-2 Spectrum Orange/CEP 17 Spectrum Green (Vysis). In brief, paraffin sections were deparaffinized, dehydrated in ethanol, and airdried. Sections were digested with protease K (0.5 mg/mL) at 37[degrees]C for 28 minutes. The slides were denatured at 75[degrees]C for 5 minutes and dehydrated in ethanol. The probes were denatured for 5 minutes at 75[degrees]C prior to hybridization. Slides were hybridized overnight at 37[degrees]C and washed in 2XSSC/0.3% NP40 at 72[degrees]C for 2 minutes. Nuclei were counterstained with DAPI/antifade I (Vysis). Each FISH assay included normal parotid gland sections as negative controls and amplified breast tissue as HER2 controls. Analyses were performed using a fluorescence microscope (Nikon Optiphot-2 and Quips Genetic Workstation; Nikon Inc, Melville, New York) equipped with Chroma Technology 83000 filter set with single band excitors for Texas Red/Rhodamine, FITC, and DAPI (ultraviolet 360 nm). The histologic areas previously selected on the hematoxylineosin-stained sections were identified on the FISH-treated slides. Only well-delineated cells were scored. At least 60 cells were scored for each case and control.
Each tumor was assessed by the average and the maximum numbers of copies of C-MYC and HER2 genes per cell and the average ratio of C-MYC and HER2 genes to chromosomes 8 and 17 copy numbers. Amplification was defined as a ratio of c-myc and her2 signals to chromosomes 8 and 17 centromere signals of 2.0 or more.
Immunohistochemical studies for p53 (clone DO7, 1:100; Dako, Carpinteria, California), cyclin D1 (clone H-295, 1:150; Santa Cruz, Santa Cruz, California), and HER2/neu (clone CB11,1:200; Novocastra, Newcastle, United Kingdom) were performed as described previously. (13) The antibody labeling was performed with the Ventana Iview DAB (2-diaminobenzidine) Detection Kit (Ventana Medical Systems, Tucson, Arizona) as the substrate chromogen (brown). Immunohistochemical results were reported qualitatively (positive or negative) for HER2/ neu and were semiquantitatively expressed to the nearest fifth percentile for cyclin D1 and p53.
The clinicopathologic features are summarized in Table 1. The mean age was 54.5 years (range, 42-64 years), and the gender distribution was even. The mean size was 3.2 cm (range, 2.7-4 cm). In all cases presented here, the conventional components were solid and relatively monomorphic (Figure 1, a) while the transformed components consisted of more pleomorphic enlarged tumor cells with a papillary, cribriform, or solid growth pattern (Figure 1, b). In primary tumors, the median percentage of transformed component was 52.5% (range, 10%-70%). The metastasis from case 2 was predominantly transformed (95%). By immunohistochemistry, the primary tumors showed a median p53 reactivity of 5% (range, 0%-5%) in the conventional components, and a median p53 reactivity of 25% (range, 5%-70%) in the transformed components (Figure 2, a and b). The conventional components showed a median cyclin D1 reactivity of 45% (range, 0%-90%), while the transformed components showed a median cyclin D1 reactivity of 65% (range, 50%-90%) (Figure 2, c and d). The metastasis was negative for p53 and showed a cyclin D1 reactivity of 75%. HER2/neu staining was negative in all cases (Figure 2, e). Half the cases (cases 1 and 2) showed local recurrence, while 1 of 2 cases (case 3) in which nodes were assessed showed nodal metastases. Half the cases showed distant metastases to the lung (case 2) and soft tissue of shoulder (case 3). Three patients died of disease with a median survival of 12 months (range, 11-12 months) from the time of initial surgery. Follow-up on the surviving patient was 9 months.
aCGH and FISH
For DNA sequence copy number losses the fluorescence ratios of tumor and reference DNA ranged from 0.44 to 0.63 and from 1.45 to 3.85 for DNA sequence copy number gains. Table 2 summarizes chromosomal gains and losses. Overall, chromosomal regions that showed significant gains were17q23 (4 of5tumors,4 of4primaries),8q24.12 q24.13 (4 of 5 tumors, 3 of 4 primaries), 15q11-13 (4 of 5 tumors, 4 of 4 primaries), 5p15.2, 17q11.2-q12, and 22q31 (2 of 5 tumors each, 2 of 4 primaries). Regions that showed the significant losses included 9q34, 4p16.3 (2 of 5 tumors each, 1 of 4 primaries), 1p36.1, and 11q22.3 (1 of 5 tumors each, 1 of 4 primaries).
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The areas of HGT (the transformed components) in all 4 primary tumors showed significant chromosomal gains (median number of regions, 3; range, 1-6), but none showed chromosomal losses. In contrast, both conventional areas in case 1 and 2 showed chromosomal losses (3 regions in case 1, 1 region in case 2), but only case 2 showed chromosomal gains in the conventional area that were also seen in the transformed component (Figure 3, a and b). Interestingly, the metastasis for case 2, which was morphologically thought to contain mostly transformed areas, showed 1 gain that was also seen in the transformed component of the primary. This metastasis also showed 2 losses that were not present in the transformed component of the primary.
Figure 4 shows FISH analysis of cases with C-MYC and HER2/neu confirming gains by hyperploidy and/or lowlevel amplification.
Cheuk et al (12) were the first to describe ACC-HGT dubbing it with the moniker "dedifferentiated ACC." In our recent clinicopathologic review of this tumor, we applied the term "adenoid cystic carcinoma with high-grade transformation" in an attempt to more accurately reflect this phenomenon because it is actually a form of tumor progression rather than regression. (24) This process has also been described in acinic cell carcinoma, epithelial-myoepithelial carcinoma, and polymorphous low-grade adenocarcinoma. (13,25-27)
Among the most striking clinical features of ACC-HGT is the high propensity for lymph node metastases present in 57.9% of cases. (12,18-20,24,28) In contrast, the reported rate of lymph node involvement in conventional ACC ranges from 5% to 25% and may include lymph nodes involved by direct extension from the primary tumor.6 Median survival for patients with ACC-HGT may be as low as 12 months. (24) In the cases analyzed here, which constituted a subset of our previously reported series, no patients survived beyond 12 months; there was only 9-months follow-up available in the surviving patient.
An understanding of the molecular alterations underlying this extremely aggressive behavior is minimal. Two classic molecular markers that have been evaluated in ACC-HGT are p53 and cyclin D1. However, not all ACCHGT show TP53 gene alterations or protein overexpression. (12,18-20,24,28) Additionally, cyclin D1 is overexpression does not effectively discriminate between ACC-HGT and pure conventional ACC. (12,18-20,23,24,28)
To date, gross chromosomal alterations have not been evaluated in ACC-HGT. In conventional ACC, the chromosomal gains and losses have been reported in at least 66 cases using methodologies ranging from conventional karyotypic analysis to metaphase comparative genomic hybridization. (29-34) The findings of these cases are summarized in Table 3. Recently, aCGH has been applied to 71 additional ACCs. (35,36) Overall, the patterns of chromosomal alterations in ACC are heterogenous; there are no specific losses or gains that define ACC. The most frequent gains are noted in chromosomes 16, 19, and 22, while the most frequent losses are noted in chromosomes 6q, 12q, and 13q. The chromosomal losses at 6q and 12q have been mapped by microsatellite loss of heterozygosity analysis to define specific regions of deletion narrowing possible candidate genes of interest.37,38 Stallmach et al (39) have also established a prognostic role for loss of heterozygosity at chromosome 6q23-25. The recent aCGH study by Vekony et al (36) demonstrated a similar frequency in gains. Losses were less frequent but chromosome 12q and 13q were still among the more commonly involved regions. Here, gains in regions 5q35, 7p22, and 16q24 correlated with the solid pattern. Additionally, alterations of 4p16, 11q23-q24, 16p13, 16q24-q24, and 17p13 correlated with recurrence/metastasis and alterations in 17 or more loci correlated with poorer survival. In contrast, in the largest aCGH study of conventional ACCs to date, (35) 1p32-p36 losses were the most frequent abnormality, found in up to 44%, although chromosome 6q23-q27 and 12q12-q14 deletions were still frequent. Interestingly, here, 1p32-p36 loss appeared to be the only comparative genomic hybridization abnormality that correlated with outcome in a significant fashion.
The heterogeneity of previously reported chromosomal alterations in conventional ACC suggests that even ACCHGT may show some heterogeneity at this level as well. For instance, our analysis was restricted to solid conventional ACC that showed areas of HGT. Our cases are different from the classic description using the older terminology "dedifferentiated ACC" as described by Cheuk et al (12) and are more along the lines of the HGT described by Sato et al.40 Although our original series contained ACC-HGT with conventional components of all grades, we did not have additional material for evaluation of cases with low-grade conventional components (tubular or cribriform). We cannot be certain whether the progression from solid ACC to ACC-HGT is reflected by the same chromosomal abnormalities as the abrupt transformation from lower grade ACC (tubular or cribriform) to ACC-HGT.
In our primary tumors, losses were mainly confined to the conventional component of ACC-HGT. None of our cases showed loss at 6q or 12q. The regions of loss in our series are, however, represented to some extent in the literature. Although we did not observe gains in chromosomes 16 or 19, two cases showed gains at 22q31. However, certain gains were noted in most or all primary tumors. The most common regions with gains in ACCHGT were 17q23, 8q24.12-q24.13, 15q11-13, and 17q11.2q12. Our aCGH analysis yielded fewer alterations per case than those of Vekony et al (36) and Rao et al. (35) This may be attributed to differences in resolution, loci tested, and stringency of criteria used to define gains or losses. Several other chromosomal alterations did not meet our threshold for significance.
[FIGURE 3 OMITTED]
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The gene C-MYC, found at chromosome 8q24 was amplified by FISH in the transformed components. The amplification of C-MYC in ACC, conventional or with HGT, has not been described by FISH or comparative genomic hybridization. However, by gene array, C-MYC was noted as one of the genes differentially expressed as compared with normal. (21) Additionally, 1 study demonstrated that the overexpression of the c-myc protein product was seen in 41.9% of ACCs and correlated with "cellular atypia." (41) However, immunoexpression results for c-myc protein do not correlate completely with gene amplification. In prostatic adenocarcinoma, although c-myc protein overexpression was found in 82% of cancer foci, extra copies of C-MYC gene were noted only in 44%. (42) Of note, 4 conventional ACCs previously reported had gains of chromosome 8, and of these, 3 were solid or grade (3.29,30,33) It is thus possible that C-MYC is involved in HGT of ACC. Other possible markers in this region such as EXT-1 and PVT-1, have not been evaluated in ACC. EXT-1 encodes the glycosyltransferase exostosin-1 involved in the development of osteochondroma and multiple hereditary exostoses. In osteochondromas, it is considered a tumor suppressor gene, with frequent loss of heterozygosity at this locus. (43) However, gains have been reported in gastroesophageal junction adenocarcinomas. (44) PVT-1 encodes a nonfunctioning RNA and has been shown to be amplified in breast and serous ovarian carcinoma cell lines.22 Using oncomine 3 (www.oncomine.org, last accessed October 30, 2008), (45) we searched previously published array datasets on conventional ACC, and, indeed, EXT-1 is among the upregulated genes in ACC, although PVT-1 is not.
Gains of chromosome 17q have been previously noted in 10 conventional ACCs. (29,30,36) In 5 of these tumors in which grade was noted on a case by case basis, tumors were tubular or cribriform patterned (grade 1-2). (29,30) Gains of chromosome 17q11.2-q12 and 17q23 were common in our cases. The major oncogene in the 17q11.2-q12 region is HER2/neu. By FISH, the 2 cases of ACC-HGT with gains of 17q11.2-q12 showed a low level of HER2/neu amplification that would be considered negative under American Society of Clinical Oncology/College of American Pathologists guidelines46 for HER2/neu FISH interpretation. By immunohistochemistry, these tumors were negative for HER2/ neu. HER2/neu expression by immunohistochemistry has only been noted in 3 previously reported ACCHGT cases, (20,40) and none were evaluated by FISH. Based on these findings, it is difficult to attribute a major contributory role of HER2/ neu in progression to ACC HCT. Another marker in this region is MAP2K3. MAP2K3 is a MAP kinase kinase family member that could potentially function as an oncogene by phosphorylating and activating p38 MAPK and MAPK14. Our query of a previous array data restricted to 17q11 (45) in conventional ACC shows that MAP2K3 is increased, as is HER2/neu, although to a lesser degree.
Putative oncogenes at 17q23 that are upregulated in the ACC dataset queried using Oncomine 3 (45) include TBX2 and PPM1D. TBX2 or T-box 2 is an antisenescence gene that is amplified in breast, pancreatic carcinoma, and melanoma. It serves as a regulator of p21. (47) PPM1D,or protein phosphatase 1D magnesium-dependent, delta isoform, suppresses phosphorylation and activation of p53 by repressing p38 MAPK. It is also noted to contribute to breast carcinogenesis by gene amplification.48 Gains of regions of chromosome 15 were only seen in 2 cases of conventional ACC previously reported, but gain in the region 15q11-13 has not been noted in conventional ACC. (29,31) The genes in this chromosomal region that are upregulated in ACC are not yet well characterized.
In summary, using aCGH, we have identified for the first time, chromosomal alterations and gene amplification events outside of p53 mutation status that may be responsible for tumor progression in ACC-HGT. The prominence of 8q24 gains implicates C-MYC amplification as another mechanism for HGT. When comparisons between the conventional solid components and the areas of HGT were able to be made, a differential profile emerged supporting the morphologic impression that HGT is indeed a distinct biologic process. Additional regions with gains, particularly chromosome 17q23, contain putative oncogenes that warrant further investigation in ACC-HGT and possibly even conventional ACC.
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Raja R. Seethala, MD; Kathleen Cieply, MS; E. Leon Barnes, MD; Sanja Dacic, MD, PhD
Accepted for publication March 26, 2010.
From the Department of Pathology and Laboratory Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Drs Seethala and Dacic and Mrs Cieply); and the Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio (Dr Barnes).
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Raja R. Seethala, MD, Department of Pathology and Laboratory Medicine, University of Pittsburgh, A616.3 PUH, 200 Lothrop St, Pittsburgh, PA 15213 (e-mail: email@example.com).
Table 1. Clinicopathologic Features of Adenoid Cystic Carcinoma (ACC) With High-Grade Transformation Case Age, y/Sex Site Size, cm 1 59/M Pterygopalatine NA 2 53/F Left nasal 4 3a 64/F Right palate 2.7 4a 42/M Right submandibular 3 Conventional ACC % Transformed p53 IHC HER2/neu Case Component Component (%) IHC (%) 1 Solid 55 5 conv Negative 70 trans 2 Solid 10 primary 0 conv Negative 5 trans 95 met 0 met 3a Solid 70 5 conv Negative 15 trans 4a Solid 50 5 conv Negative 35 trans Abbreviations: -, negative;+, positive;conv, conventional;DOD, died of disease;IHC, immunohistochemistry;met, metastasis;NA, not available; NED; no evidence of disease; trans, transformed. (a) Follow-up updated from initial series (13). (b) Clinical status, no dissection performed. Table 2. Chromosomal Gains and Losses Confirmed by Fluorescence In Situ Hybridization Case Gains Losses 1 conventional 1p36.31 4p16.3 9q34 1 transformed 17q23 2 primary 15q11-q13 11q22.3 conventional 17q23 2 primary 8q24.12-q24.13 transformed 15q11-q13 17q23 2 metastasis 8q24.12-q24.13 4p16.3 9q34 3 5p15.2 8q24.12-q24.13 15q11-q13 17q11.2-q12 17q23 22q31 4 5p15.2 8q24.12-q24.13 15q11-q13 17q11.2-q12 17q23 22q31 Table 3. Most Frequent Chromosomal Imbalances in 66 Previously Reported Cases of Conventional Adenoid Cystic Carcinoma Chromosomal Arm Frequency of Alteration, % Gains 16p 16.67 16q 13.64 19p 9.09 19q 10.61 22p 13.64 22q 18.18 Losses 6q 28.79 12q 15.15 13q 10.61
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|Author:||Seethala, Raja R.; Cieply, Kathleen; Barnes, E. Leon; Dacic, Sanja|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Jan 1, 2011|
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