MYB Gene Abnormalities t(6;9) in Adenoid Cystic Carcinoma Fine-Needle Aspiration Biopsy Using Fluorescence In Situ Hybridization

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1 MYB Gene Abnormalities t(6;9) in Adenoid Cystic Carcinoma Fine-Needle Aspiration Biopsy Using Fluorescence In Situ Hybridization Jena B. Hudson, MD; Brian T. Collins, MD Context. Fine-needle aspiration (FNA) biopsy of salivary gland neoplasms can have a variety of overlapping appearances. Basaloid neoplasms can be a diagnostic challenge, and FNA cytomorphology alone cannot always provide a definitive diagnosis. Objective. To examine the incidence and potential utility of detecting a MYB translocation by fluorescence in situ hybridization (FISH) in adenoid cystic s (AdCCs) and pleomorphic FNA smears with known surgical outcomes. Design. Patients who underwent FNA biopsy for surgically confirmed AdCCs and pleomorphic s were identified. Fluorescence in situ hybridization, using commercially available fluorescent-labeled probes, hybridizing to MYB-telomeric and MYB-centromeric, was used to identify the MYB gene and to evaluate it for abnormalities and translocation. Using a fluorescent microscope, 4 0,6- diamidino-2-phenylindole (DAPI)-stained, nonoverlapping cells were counted, and 10% or greater abnormal cells were considered positive. Results. The 10 AdCC and 13 pleomorphic FNA cases had FISH evaluations performed; 50% (5 of 10) of the AdCC cases showed a MYB abnormality by FISH; 40% (4 of 10) AdCCs showed a positive break-apart signal in most cells (48% 84%). One case (10%) of AdCC showed a trisomy MYB signal pattern without the breakapart translocation pattern. Of the 13 pleomorphic s, none (0%) of the cases showed a MYB translocation or abnormality by FISH. MYB FISH abnormalities showed a 100% positive predictive value, 50% sensitivity, and 100% specificity, when differentiating AdCC from pleomorphic. Conclusions. MYB gene abnormalities were present in 50% (5 of 10) of the AdCC cases. This corresponds to the reported prevalence in formalin-fixed, paraffin-embedded tissue for AdCC surgical resections. Using FISH testing for detecting MYB gene abnormalities in the salivary gland of FNA biopsies has the potential to provide additional, helpful ancillary information in diagnosing AdCC. (Arch Pathol Lab Med. 2014;138: ; doi: / arpa oa) Adenoid cystic s (AdCCs) are infrequently encountered malignant neoplasms of the salivary glands that can present difficulties in specific preoperative diagnosis by fine-needle aspiration (FNA) biopsy. On aspirate smears, they frequently show small, round, bland nuclei without the typical features of malignancy noted in other s (nuclear enlargement, marked atypia, and pleomorphism). They can aggregate in small, 3-dimensional, tight groups with a background showing varying amounts of dense, matrixlike material. This general pattern overlaps with other benign and malignant basaloid-type salivary gland neoplasms, with the primary differential considerations being pleomorphic (PA) and, lesscommonly, basal cell and basal cell. These entities can often have indistinguishable, overlapping Accepted for publication May 14, From the Department of Pathology and Immunology, St Louis School of Medicine, Washington University, St Louis, Missouri. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Brian T. Collins, MD, St Louis School of Medicine, Washington University, Campus Box 8118, 660 S Euclid Ave, St Louis, MO ( bcollins@path.wustl.edu). morphologic features, and although subtle differences can be noted, they are insufficient for a clear, definitive distinction on FNA biopsy. This typically results in a descriptive FNA biopsy diagnosis and is reported as a basaloid neoplasm with a comment detailing the differential diagnostic possibilities and limitations of definitive classification because of the morphologic appearance. 1,2 Currently, there are few ancillary studies available to assist in the differential diagnosis of salivary gland basaloid neoplasms on FNA biopsy. CD117 is a sensitive immunohistochemical marker for AdCC, but it can stain nearly 20% of benign PAs, the most common neoplasm of the salivary gland and the most frequent differential diagnosis for a basaloid neoplasm. 3 Recently, cytogenetic abnormalities involving a t(6;9) (q22-23;p23-24) translocation have been described in adenoid cystic of the salivary glands. 4 The translocation involves the gene encoding the transcription factor MYB. Importantly, other salivary gland neoplasms, including PA, lack the MYB translocation, making a MYB gene abnormality specific to AdCC. 5,6 These studies have been performed on formalin-fixed, paraffinembedded, surgically excised neoplasms studied with fluorescent in situ hybridization (FISH) break-apart probes for the MYB gene. Arch Pathol Lab Med Vol 138, March 2014 MYB in ACC FNA FISH Hudson & Collins 403

2 Detecting a MYB translocation in a FNA biopsy specimen with the morphologic diagnosis of basaloid neoplasm could provide a more precise preexcision diagnosis of AdCC. The aim of this study was to examine the incidence and utility of detecting a MYB translocation in AdCC and PA FNA smears with known surgical outcomes. MATERIALS AND METHODS The pathology database at Washington University Medical Center (St. Louis, Missouri) was searched for patients with known adenoid cystic confirmed by surgical excision, who had undergone FNA biopsy for a 10-year consecutive period. An ageand case-matched control case series of pleomorphic cases with predominantly basaloid appearance and confirmation by surgical excision was selected. Pertinent clinical and pathology information from the cases was collected. The cases identified were retrospectively reviewed in combination with the available clinical and pathologic history. Histologic grading/subtyping of resection specimens was performed. 7 9 All FNA biopsies were processed in a paired manner with air-dried smears stained by a modified Wright- Giemsa method, and the alcohol-fixed smears were stained by the Papanicolaou method. Representative air-dried, modified Wright- Giemsa slides from each case were identified and used for the FISH study. A FISH break-apart assay was designed using 2 bacterial artificial chromosome probes flanking the MYB gene (RP11-104D9- centromeric, RP M6-telomeric) (Empire Genomics, Buffalo, New York). Wright-Giemsa slides were immersed in xylene until coverslips were easily removed. Slides were then destained with a series of alcohol baths (100%, 95%, and 70%, 3 minutes each) and then submerged in ice-cold Carnoy solution for 10 minutes, followed by phosphate-buffered saline for 5 minutes and air dried. The slides were then treated according to the Vysis UroVysion protocol (Abbott Laboratories, Abbott Park, Illinois) by immersion in 23 sodium, saline, citrate stock solution at 738C for 2 minutes, followed by protease solution at 378C for 10 minutes, then placed for 5 minutes in each of phosphate-buffered saline, 1% formaldehyde, and phosphate-buffered saline again. Next, the slides were dehydrated with a series of ethanol washes for 1 minute each (70%, 85%, 100%) and air dried. Three microliters of probe mixture was applied to a previously selected area of the slide (etched with a diamond-tipped pen) and covered with a 12-mm round coverslip. Rubber cement was applied to the coverslip margin to prevent dehydration. The slides were codenatured in a slide moat at 738C for 5 minutes and then placed at 378C for 16 hours for hybridization. The following day, the slides were decoverslipped, washed in 0.43 sodium, saline, citrate stock solution, and 0.3% Tergitol-type NP-40 (NP-40) at 738C for 2 minutes, washed in 23 sodium, saline, citrate stock solution 0.1% NP-40 at room temperature for 1 minute and left to dry in the dark. The slides were counterstained with 10 ll of 4,6-diamidino 2-phenylindole (DAPI) for microscopy. Signals were interpreted manually, and images were captured by using the CytoVision software (Leica Microsystems, Buffalo Grove, Illinois). Depending on the degree of cellularity, a range of 10 to 50 cells per case with probe were counted manually under 3100 objective in a continuous manner, whenever possible. Inflammatory cells and macrophages were not counted. Specifically, only bright, compact signals having similar fluorescent intensity were counted, whereas overlapping nuclei, such as those in clusters, were not counted. Two signals that were located within a distance of less than the diameter of one signal were counted as one signal. Furthermore, to avoid so-called artifactually hyperdiploidy, such as that seen in binucleated or multinucleated cells or cell clumping, signal counting was carefully conducted by frequently changing the filters to the DAPI filter, on which nuclear outlines can be seen easily. For data analysis, a case having a MYB break-apart for one gene signal per nucleus in more than 10% of the total cells counted was considered to represent translocation (this cutoff was arbitrarily designated before analysis). Statistical analysis was calculated for sensitivity, specificity, positive predictive value, and negative predictive value, based on standard formulas. The study was performed with the approval of the institutional review board. RESULTS Ten patients with surgically confirmed adenoid cystic who had FNA biopsies were identified. The patients ranged in age from 22 to 92 years, with 7 women (70%) and 3 men (30%). Three cases (30%) represented primary FNA biopsy, 6 cases (60%) represented metastatic disease, and one case (10%) was a local recurrence. Seven cases (70%) originated from the head and neck salivary glands, one (10%) was from the bronchopulmonary tree, and 2 (20%) were from the lower female genital tract. See Table 1 for a summary of clinical, cytologic, and histologic characteristics. There were 13 PA FNA biopsy cases, which were all parotid or submandibular based in anatomic location. The clinical, cytologic, and histologic characteristics are described in Table 2. The specific MYB FISH result for each AdCC is presented in Table 3. There were 4 cases (4 of 10; 40%) with translocation of the MYB gene by FISH evaluation. Figure 1 shows a representative, positive MYB break-apart signal (case 2). Figure 2 shows a side-by-side comparison of the FNA smear, MYB FISH break-apart study, and histologic resection for an AdCC with a positive MYB break-apart signal (case 5, Figure 2, A, C, and E) next to an AdCC with a negative MYB break-apart signal (case 4, Figure 2, B, D, and F). There was one AdCC case (10%) where the MYB gene showed trisomy (case 10) without break-apart translocation. See Figure 3, A, C, and E, for images of this cytology specimen, MYB FISH break-apart study, and histologic resection. At least 50 cells were counted (when present), and the abnormalities were quantitated per case. When there were fewer than 50 cells discernible by DAPI stain, then all cells were examined, and the MYB FISH signals were recorded. Slides with more than 10% of cells showing MYB abnormality were considered positive, and the relative positive rate ranged from 48% to 84%. For all PA cases (13 of 13; 100%), at least 50 cells were examined, and all cells showed 2 copies of the MYB gene (break-apart probe) without translocation or trisomy. Figure 3, B, D, and F, demonstrate a typical PA case: FNA smear, MYB FISH break-apart study, and resection specimen. MYB FISH abnormalities in AdCC and PA FNA biopsy demonstrated a sensitivity of 50% (95% confidence interval [95% CI], 19 81), a specificity of 100% (95% CI, ), a positive predictive value of 100% (95% CI, ), and a negative predictive value of 72% (95% CI, 47 90). Three of the 4 AdCCs (75%) that were positive for the MYB breakapart were grade 2 and the cribriform subtype. Four out of the 5 AdCCs (80%) with no MYB abnormality were grade 3 and the solid subtype. The case (10%) that was triploid for MYB signals was a grade 2/cribriform AdCC. COMMENT The FNA biopsy of salivary gland lesions has proven useful for the evaluation and management of patients. Within the wide spectrum of entities encountered in salivary gland neoplasms, FNA biopsy is frequently able to render a specific diagnosis that helps the patient and clinicians determine subsequent follow-up and treatment. Nevertheless, this diversity of entities, with a variety of patterns and 404 Arch Pathol Lab Med Vol 138, March 2014 MYB in ACC FNA FISH Hudson & Collins

3 Case No. Table 1. Clinical, Fine-Needle Aspiration (FNA) Biopsy, and Histologic Features of Adenoid Cystic Carcinomas Age, y/sex FNA Biopsy Site FNA Diagnosis 1 78/F Lung (met, salivary gland primary) Metastatic adenoid cystic 2 63/M Liver (met, lung primary) Metastatic adenoid cystic 3 38/M Lung (met, salivary gland Metastatic adenoid cystic primary) 4 49/F Liver (met, salivary gland Malignant cells, consistent primary) with patient s history of AdCC Histologic Diagnosis (Subtype) Lung: metastatic AdCC, cribriform pattern, grade 2 (met) (primary) AdCC, cribriform pattern, grade 2 (primary) AdCC, solid pattern grade 3 (primary) 5 52/F Lung (met, vulvar primary) Adenoid cystic Metastatic AdCC, cribriform pattern, grade 2 (met) 6 60/M Parotid (primary) Poorly differentiated 7 22/F Parotid (primary) Atypical cytology (basaloid neoplasm ddx) AdCC, cribriform pattern, grade /F Breast (primary) Suspicious for malignancy (AdCC versus collagenous spherulosis) 9 84/F Paraesophageal/paratracheal (recurrence) Positive for well differentiated (ddx includes AdCC versus well diff papillary adeno) 10 92/F Liver (met, cervical primary) Positive for malignancy,, consistent with history of AdCC Abbreviations: AdCC, adenoid cystic ; ddx, differential diagnosis; met, metastasis; well diff, well differentiated. (recurrence) Invasive adenoid cystic, cribriform pattern, grade 2 (primary) similar-appearing cell types, can present a significant challenge in precise diagnosis. One of the main challenges is the basaloid neoplasm pattern, which is generally characterized by an FNA aspirate that demonstrates a cellular population of small cells aggregated in loosely cohesive groups with scant to absent background mesenchymal material (see Figures 2, A and B; 3, A and B). The primary differential diagnostic considerations within the basaloid neoplasm pattern include adenoid cystic, monomorphic, and pleomorphic / predominant basaloid appearance. Many authors have described the subtle morphologic features that can help differentiate these entities. To some degree, these features have proven to be subjective and difficult to apply accurately and consistently for reproducible diagnosis. The cytomorphologic appearance alone does not always permit a definitive diagnosis. Therefore, a descriptive diagnosis of basaloid neoplasm is appropriate, combined with a comment discussing the differential diagnostic considerations. Chromosomal instability is a nearly universal hallmark of the cancer genome that results in aneuploidy and/or structural chromosomal abnormalities. 14,15 Recent reports 5,6 have described MYB translocation in a significant proportion of AdCCs. The aim of this study was to determine the incidence of MYB translocations in AdCC by FISH using direct FNA smears and to compare that rate to the incidence Case No. Table 2. Clinical, Fine-Needle Aspiration (FNA) Biopsy, and Histologic Features of Pleomorphic Adenomas Age, y/sex FNA Biopsy Site FNA Diagnosis Histologic Diagnosis (Subtype) 1 41/F Right parotid Positive for neoplasm, consistent Pleomorphic (classic) with pleomorphic 2 55/F Right parotid Pleomorphic Pleomorphic (myxoid) 3 64/M Right parotid Pleomorphic Pleomorphic (classic) 4 45/M Right parotid Pleomorphic Pleomorphic (cellular) 5 27/M Left parotid Pleomorphic Pleomorphic (classic) 6 42/M Left parotid Positive for neoplasm, features of Pleomorphic (classic) benign mixed tumor 7 62/M Right submandibular Consistent with pleomorphic Pleomorphic (classic) 8 42/F Right parotid Consistent with pleomorphic Pleomorphic (classic) 9 40/F Left parotid Pleomorphic Pleomorphic (cellular) 10 64/M Right parotid Pleomorphic Pleomorphic (classic) 11 46/M Right submandibular Consistent with pleomorphic Pleomorphic (cellular) 12 28/M Right parotid Pleomorphic Pleomorphic (classic) 13 74/F Right parotid Consistent with pleomorphic Pleomorphic (cellular) Arch Pathol Lab Med Vol 138, March 2014 MYB in ACC FNA FISH Hudson & Collins 405

4 Table 3. MYB Translocation t(6;9) in Adenoid Cystic Carcinoma Fine-Needle Aspiration Biopsy Using Fluorescence In Situ Hybridization: Adenoid Cystic Carcinoma Cases Case No. Total Cell Count, No. MYB Abnormal Cells, No. (%) a (54) a (84) (0) (0) a (72) (0) a (50) (0) (0) b (48) a MYB translocation. b MYB trisomy. in PA, the most common differential diagnosis for AdCC. Persson et al 5 described a recurrent t(6;9) translocation in adenoid cystic of the breast and salivary gland. The translocation leads to fusion of the MYB gene with new gene partners, frequently the nuclear factor 1 B-type (NFIB) transcription factor. 5 The fusion leads to deregulation of the expression of MYB, which likely contributes to the neoplastic process in AdCC. The MYB gene is related to cell development and differentiation. 16 Its involvement in human oncogenesis is less well understood. Ten cases of AdCC, sampled by FNA, were studied and 5 (50%) showed MYB abnormalities by FISH. Four cases (40%) showed MYB translocation in most cells examined. When up to 50 cells were counted (when present), the MYB translocation was noted in 48% to 84% of cells. One case (10%) showed MYB trisomy and lacked evidence of MYB translocation. There were 13 pleomorphic s studied, and all these cases (100%), lacked the MYB translocation. In this case-controlled study, a MYB FISH abnormality had a positive predictive value of 100%, a specificity of 100% with 50% sensitivity, and a 72% negative predictive value, when the differential diagnosis was pleomorphic. West et al 6 showed that MYB translocation was present in 49% (18 of 37) of patients with AdCC by FISH in formalinfixed, paraffin-embedded resection material and 16% (6 of 37) of the AdCC cases had abnormal MYB FISH patterns. Our percentages of MYB abnormalities were similar to the overall findings of West et al. 6 In their study, MYB abnormalities were absent in other salivary gland lesions (112 salivary gland neoplasms and 409 nonsalivary gland neoplasms). 6 Because there were limited numbers of AdCC FNAs with adequate cellularity, AdCCs arising from the lung, cervix, vulva, and breast were also included. In this study, the tumors with MYB abnormalities were from a variety of primary sites: 2 salivary gland primaries (20%), one lung primary (10%), and one vulvar primary (10%). The case that was triploid for MYB signals arose from the cervix. The number of cases in this study is too small to make a correlation between MYB translocation and histologic grade, but in this small series, grade 2 tumors were more likely to have a MYB translocation than were grade 3 tumors. Because of the indolent nature of these tumors, 2 of the metastatic foci that were biopsied by FNA, subsequently Figure 1. Fluorescence in situ hybridization (FISH) break-apart, bicolor pattern in adenoid cystic (red, 3 0 MYB; green, 5 0 MYB). The red and green signals are split, indicating translocation. When they are adjacent, the overlap imparts a yellow coloration. The figure also shows 2 adjacent neutrophils without translocation (bicolor FISH probe with DAPI counter stain, original magnification 3100). resected, and used for this study were discovered many years after the primary tumors, which were not available for review. The PAs were included as the only controls because of their availability in the slide archives. Other tumors from the basaloid neoplasm category, such as basal cell and basal cell, were not available to use. We believe it is reasonable to extrapolate from previous studies that showed no MYB abnormalities in other salivary gland tumors in the basaloid neoplasm category on formalin-fixed, paraffin-embedded tissue to cytology specimens. 6 We can corroborate their finding of no MYB abnormalities in PAs. Because this is a retrospective analysis, it is not possible to know how the availability of this testing would affect clinical care. As a conservative estimate, there were 4 final cytologic diagnoses (40%) where AdCC was in the differential but could not be confirmed. Of those 4 cases, 1 (25%) (case 7) had a MYB translocation, which would have provided a definitive final diagnosis. In cases where an abnormal MYB FISH pattern was seen, a high proportion of the aspirated cells examined showed the abnormality (48% 84%). West et al 6 used a cutoff of 30% to define a positive MYB translocation in formalinfixed, paraffin-embedded tissue. All our positive cases would have remained positive with that cutoff as well. The high percentage of break-apart signals in each case suggests that this technique could be applied to smears with lower cellularity. However, standards for cellularity cutoffs would need to be validated in a larger series and is outside the scope of this article. A positive MYB abnormality was only seen in patients with AdCC and had a positive predictive value of 100%. Although this is a small, case-controlled study, performed retrospectively, the finding of a MYB FISH abnormality suggests the diagnosis of AdCC on FNA biopsy. Because immunostain options to differentiate the basaloid neo- 406 Arch Pathol Lab Med Vol 138, March 2014 MYB in ACC FNA FISH Hudson & Collins

5 Figure 2. Adenoid cystic s with and without MYB break-apart signal. A, C, and E are from case 5, and B, D, and F are from case 4. A and B, The cytologic appearance (aspirate smear, air dried) of the metastatic adenoid cystic. C and D, The corresponding fluorescence in situ hybridization (FISH) break-apart study (red, 3 0 MYB; green, 5 0 MYB). C, Positive for the MYB break-apart signal. D, Negative for a break-apart signal. E and F, The corresponding resection specimens (modified Wright-Giemsa, original magnifications 340 [A and B]; bi-color FISH probe with DAPI counterstain, original magnifications 3100 [C and D]; hematoxylin-eosin, original magnifications 320 [E and F]). plasms are limited and because MYB translocation appears to be specific to AdCC, the use of FISH for MYB translocation could be diagnostically useful when the differential diagnosis includes AdCC. West et al 6 has shown that MYB can be evaluated by immunohistochemistry and that strong MYB staining is specific to AdCC but is present in only 65% of cases. Use of this methodology also has potential to assist in the differential diagnostic consideration of basaloid neoplasms sampled by FNA biopsy. A cell block with adequate cellularity could provide material for a variety of supportive ancillary testing methodologies. Additionally, MYB positivity in AdCC has shown a correlation with more aggressive biologic behavior. 6 The MYB FISH abnormality shows promise in providing the ability to further narrow the differential diagnosis and in guiding the treating clinicians. Various factors contribute to the management of patients with salivary gland lesions diagnosed as a basaloid neoplasm on FNA biopsy. The size of the lesion; its location, clinical history, and imaging Arch Pathol Lab Med Vol 138, March 2014 MYB in ACC FNA FISH Hudson & Collins 407

6 Figure 3. A, C, and E, Adenoid cystic from case 10. B, D, and F, Typical pleomorphic. A, Cytology specimen from the liver metastasis (aspirate smear, air dried). C, Fluorescence in situ hybridization (FISH) study for MYB gene abnormalities (red, 3 0 MYB; green, 5 0 MYB) and shows 3 signals/cell but no break-apart signal. E, The corresponding primary tumor. B, The cytology specimen for a pleomorphic in the parotid (aspirate smear, air dried). D, The negative MYB FISH test on the corresponding aspirate material (red, 3 0 MYB; green, 5 0 MYB). F, The corresponding resection specimen (modified Wright-Giemsa, original magnifications 340 [A and B]; bicolor FISH probe with DAPI counterstain, original magnifications 3100 [C and D]; hematoxylin-eosin, original magnifications 320 [E and F]). appearance; and the clinical findings, such as pain or nerve impairment, can guide the physician in determining subsequent therapeutic decisions. This study indicates that the presence of a MYB FISH abnormality in a lesion diagnosed as a basaloid neoplasm by FNA biopsy could be a useful ancillary diagnostic tool to further guide surgeons preoperatively in treating patients. References 1. Faquin WC, Powers CN. Basaloid tumors: basal cell and basal cell adeno. In: Faquin WC, Powers CN, Sidaway MK, eds. Salivary 408 Arch Pathol Lab Med Vol 138, March 2014 MYB in ACC FNA FISH Hudson & Collins

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