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1 Differentiation of Malignant Melanoma From Benign Nevus Using a Novel Genomic Microarray With Low Specimen Requirements Wells M. Chandler, MD; Leslie R. Rowe, MS; Scott R. Florell, MD; Mona S. Jahromi, BS, FASCP; Joshua D. Schiffman, MD; Sarah T. South, PhD N Context. Histologic examination of clinically suspicious melanocytic lesions is very sensitive and specific for the detection of malignant melanoma. Yet, the malignant potential of a small percentage of melanocytic lesions remains histologically uncertain. Molecular testing offers the potential to detect the genetic alterations that lead to malignant behavior without overt histologic evidence of malignancy. Objective. To differentiate benign melanocytic nevi from malignant melanoma and to predict the clinical course of melanocytic lesions with ambiguous histology using a novel genomic microarray. Design. We applied a newly developed single-nucleotide polymorphism genomic microarray to formalin-fixed, paraffin-embedded melanocytic lesions to differentiate benign nevi (n = 23) from malignant melanoma (n = 30) and to predict the clinical course of a set of histologically ambiguous melanocytic lesions (n = 11). Results. For cases with unambiguous histology, there was excellent sensitivity and specificity for identifying malignant melanoma with this genomic microarray (89% sensitivity, 100% specificity). For cases with ambiguous histology, the performance of this genomic microarray was less impressive. Conclusions. Without microdissection and with quantities of DNA one-tenth what is required for more commonly used microarrays, this microarray can differentiate between malignant melanoma and benign melanocytic nevi. For histologically ambiguous lesions, longer clinical follow-up is needed to confidently determine the sensitivity and specificity of this microarray. Some of the previous technical hurdles to the clinical application of genomic microarray technology are being overcome, and the advantages over targeted fluorescence in situ hybridization assays currently in clinical use are becoming apparent. (Arch Pathol Lab Med. 2012;136: ; doi: / arpa oa) Accepted for publication November 14, From the Department of Dermatopathology, Dominion Pathology Laboratories, Norfolk, Virginia (Dr Chandler); the Department of Research and Development, ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah (Ms Rowe); the Department of Dermatology and Dermatopathology, Health Sciences (Dr Florell), the Department of Oncological Sciences, Huntsman Cancer Institute (Ms Jahromi), the Department of Pediatric Hematology Oncology, Huntsman Cancer Institute Center for Children s Cancer (Dr Schiffman), and the Department of Pathology and Pediatrics, ARUP Laboratories (Dr South), University of Utah, Salt Lake City. A single case from this study was presented as an oral abstract at the 14th Joint Meeting of the International Society of Dermatopathology, February 2, 2011, New Orleans, Louisiana. A poster describing the microarray platform and its use for detecting copy number changes in melanocytic lesions was presented at the Association for Molecular Pathology Annual Meeting, November 18, 2010, San Jose, California. A poster describing a loss of heterozygosity and copy number changes in melanocytic lesions has been accepted for presentation at the 8th European Cytogenetics Conference, July 2 5, 2011, Porto, Portugal. Dr Schiffman is a scientific consultant for Affymetrix (Santa Clara, California) and occasionally receives honoraria for talks related to OncoScan. The other authors have no relevant financial interest in the products or companies described in this article. Reprints: Wells M. Chandler, MD, Dominion Pathology Laboratories, 733 Boush St, Ste 200, Norfolk, VA ( wellsmchandler@ gmail.com). Approximately 2% of the United States population ( individuals) will be diagnosed with malignant melanoma during their lifetime. 1 Rendering the diagnosis of malignant melanoma is currently a 2-tiered process beginning with a history and visual inspection and ending with a microscopic examination. This screening and confirmatory testing algorithm results in good sensitivity and specificity; however, several studies have demonstrated room for improvement. 2 5 The seminal works by Bastian et al, 6,7 Dalton et al, 8 and Gerami et al 9 provided hope that adding a molecular test as a third tier for diagnostically challenging melanocytic lesions could increase both sensitivity and specificity and improve the accuracy of clinical prognostication. We analyzed archived formalin-fixed, paraffin-embedded (FFPE) skin biopsies of 64 melanocytic lesions (23 benign nevi, 27 primary malignant melanomas, 3 metastatic melanomas, and 11 melanocytic lesions of uncertain malignant potential [MLUMPs]) with a probe single-nucleotide polymorphism (SNP) genomic microarray (GMA) to determine if gains and losses of chromosomal material could predict benign or malignant clinical behavior. Our results indicate that SNP-GMA is a sensitive and specific method for identifying malignant melanoma when the histology is unambiguous. For samples with an uncertain histologic diagnosis, we were able to detect copy number Arch Pathol Lab Med Vol 136, August 2012 Melanoma Microarray Chandler et al 947
2 Diagnosis, Clinical Follow-Up, and Genomic Microarray Designation of Melanocytic Lesions of Uncertain Malignant Potential Diagnosis a Anatomic Location Age at Biopsy, y/sex Length of Follow-up, y Clinical Outcome Consensus Array Call Severely atypical compound melanocytic neoplasm, worrisome for nevoid melanoma Postauricular 18/F 0.2 SLN+ N Unusual Spitz nevus Cheek 33/F 0.1 LTFU N Compound Spitz nevus with mild atypia Thigh 40/F 0 LTFU N Favor malignant melanoma in situ developing within a Spitz Shin 37/F 6.5 NED N Somewhat markedly atypical Spitz nevus Calf 23/M 3 NED MM Atypical compound Spitz nevus Knee 45/F 5.5 NED N Compound spitzoid melanocytic lesion of indeterminate biologic potential Lower abdomen 24/M 3.8 NED N Favor malignant melanoma [with Spitz features] Upper back 35/M 3.2 OPM MM Ulcerated, mitotically active Spitz nevus Midfoot 5/M 0 LTFU N Atypical spindle and epithelioid cell nevus (Spitz) Anterior calf 49/F 16.4 NED MM Atypical epithelioid and spindle cell dermal [melanocytic] neoplasm Lower back 4/M 0 LTFU MM Abbreviations: LTFU, lost to follow-up; MM, malignant melanoma; N, benign nevus; NED, no evidence of additional related disease; OPM, other primary melanomas; SLN+, positive sentinel lymph node biopsy. a Diagnosis rendered by the dermatopathologist at the time of biopsy. Text in brackets [] was not in the diagnostic line, but was mentioned elsewhere in the report. b Designation rendered by participating authors based solely upon the single-nucleotide polymorphism genomic microarray whole-genome view for the sample. changes consistent with melanoma in a subset; however, the available clinical follow-up for all of these patient samples was uneventful. Nevertheless, the correlation of genomic results with the histologic classification is impressive in this initial study set, along with the ability to achieve high-quality results using limited amounts of DNA from archived FFPE specimens. MATERIALS AND METHODS Identification of Cases This study was approved by the University of Utah (Salt Lake City) Institutional Review Board, and institutional guidelines regarding the use of archived specimens and patient chart review were followed. Cases of benign nevus, malignant melanoma, and MLUMP were identified by natural language search of digitized diagnostic reports from 1991 to 2009 at the University of Utah Department of Dermatology. All diagnoses were rendered by board-certified dermatopathologists. Terms used to identify MLUMPs were atypical AND Spitz as well as favor AND melanoma. Malignant melanomas were identified using the term melanoma AND Clark IV, targeting large lesions with a high likelihood of malignant behavior. The hematoxylin-eosin stain slides of candidate cases were reviewed (by W.M.C.) and cases were excluded if there was a dense lymphocytic infiltrate, if the specimen was judged to be too small (qualitative judgment), or if the percentage of melanocytic nuclei was judged to be below 40%. After selection, digital microscopic images of the samples were analyzed. The smallest specimen had a surface area of 6.2 mm 2 and the mean surface area of all specimens was approximately 24 mm 2 equivalent to a mm shave biopsy bisected. Sixty-four melanocytic lesions were included in this study: 23 benign nevi, 27 primary malignant melanomas, 3 metastatic melanomas (all from different body sites on the same patient) and 11 MLUMPs (Table). Clinical features of patients including outcome data were not used to select cases. In the later stages of the study, samples from benign nevi with less than 250 ng of DNA (in 45 ml of solution) were excluded, as were samples of malignant melanoma and MLUMP with less than 150 ng of DNA, although some samples in the earlier stages had only 50 ng of DNA and still produced robust results. Clinical Follow-up Data After cases were identified, the University of Utah s electronic medical record was searched to identify the surgical treatments received and clinical outcomes related to the melanocytic lesions. When electronic records were unavailable or the last follow-up appointment was remote, paper records from the University of Utah Department of Dermatology were searched. DNA Extraction and Quantification Eight sections, each 10 mm thick, were taken of the archived FFPE tissue blocks used for clinical diagnosis. There was no microdissection of the FFPE specimens. DNA was extracted and purified using the Ambion RecoverAll Total Nucleic Acid Isolation kit (Applied Biosystems, Carlsbad, California) following the manufacturer s recommended protocol, with the exception of extending the protease digestion time up to 90 hours for larger specimens. Briefly, the procedure entails deparaffinization with xylene, protease digestion, ethanol, and filter cartridge based DNA isolation followed by an on-filter RNase treatment and elution. Excluding the time required for protease digestion, the time to complete the remaining steps of DNA isolation is 1 hour and 15 minutes. Extracted DNA was quantified using Quant-iT PicoGreen ds DNA HS reagent and Qubit fluorometer (Invitrogen, Carlsbad, California) following the manufacturer s package insert procedure. Briefly, 1 ml of sample was mixed with 199 ml of Quant-iT working solution, vortexed for 3 seconds, incubated at room temperature for 2 minutes, and assayed on the Qubit fluorometer. Hybridization and Data Analysis Genomic microarray hybridization was performed by Affymetrix Research Services Laboratory through the OncoScan FFPE Express Service (Affymetrix, Santa Clara, California). Technical documentation is available on the Affymetrix website. 10 Briefly, this microarray uses molecular inversion probes targeting SNPs spanning the genome to identify changes in copy number and loss of heterozygosity. The OncoScan FFPE Express assay has been designed to work with DNA from FFPE tissue and involves 2 rounds of PCR amplification. The design and performance of the molecular inversion probe GMA has been described extensively by other authors Formalin-fixed, paraffin-embedded particle clots from normal bone marrow aspirates without disease (individuals unrelated to this study cohort) were used to generate control probe signal values. Data generated by Affymetrix (probe signal intensity and genome location) were analyzed at the University of Utah using Nexus Copy Number v5.1 (BioDiscovery, El Segunda, 948 Arch Pathol Lab Med Vol 136, August 2012 Melanoma Microarray Chandler et al
3 Figure 1. Genome-wide view of probe signal intensity for a benign melanocytic nevus. There are no significant gains or losses of chromosomal material (upper plot) or loss of heterozygosity (lower plot). The y-axis of the upper plot is the number of copies, with normal diploid (2 copies) normalized to 0. The y-axis of the lower plot is dominant allele frequency, with.5 representing a heterozygous state and 1 representing a homozygous state. The x-axis is the chromosome number. California). Initial processing of the data was done with the SNP- FASST2 segmentation algorithm, a hidden Markov model based approach, in conjunction with quadratic wave correction. A minimum of 3 probes were required to create a segment. Study authors (W.M.C., L.R.R., M.S.J., J.D.S., and S.T.S.) familiar with the literature concerning genomic changes in malignant melanoma and the performance of the microarray reviewed the genome-view dot plots blinded to histologic diagnosis to render a GMA-based diagnosis of malignant melanoma, benign melanocytic lesion, or uncertain. In cases where there was not unanimity, a majority diagnosis was used. RESULTS Of 23 benign nevi, 1 had an abnormal SNP-GMA pattern, with an isolated loss of genetic material on the proximal long arm of chromosome region 12q13-q14 of 21 Mb, a pattern not reported in malignant melanomas. There were no benign nevi (Figure 1) with an SNP-GMA pattern consistent with malignant melanoma (100% specificity). All of the patients with benign nevi had an uneventful clinical course. Of the 27 primary malignant melanoma samples analyzed, 24 showed gains or losses characteristic of malignant melanoma (89% sensitivity; Figure 2) and 1 showed changes that were indeterminate by consensus (Figures 3 and 4). Chromosomal gains characteristic of malignant melanoma frequently involved segments of the following chromosomal arms: 6p (67%), 7q (48%), 7p (33%), 1q (15%), and 8q (15%). Chromosomal losses characteristic of malignant melanoma frequently involved segments of the following chromosomal arms: 9p (59%), 9q (56%), 10q (37%), 10p (33%), 6q (26%), 5q (26%), 14q (22%), 3q (19%), 11q (19%), 16q (19%), 1p (15%), and 11p (15%). Two melanoma samples displayed copy number neutral loss of heterozygosity, involving 9p in one sample (Figure 5) and 10p and 10q in the other. Ten of the 27 patients with malignant melanoma had a more aggressive melanoma characterized by the development of metastatic disease in the form of a positive lymph node (including sentinel lymph node [SLN]) or in-transit or distant metastases. Nine of 10 (90%) of these more aggressive melanomas were identified by SNP-GMA. Of the 3 metastatic melanoma samples from the same patient, 2 samples showed a similar pattern of gains and losses characteristic of malignant melanoma. The third remaining metastatic melanoma sample showed a pattern of low-amplitude gains and losses, which blinded consensus did not initially designate as melanoma; however, when viewed in light of the patient s other metastatic samples, the faint pattern of gains and losses was similar and was sufficient to designate this third sample as metastatic melanoma arising from the same clone. Of the 11 MLUMPs analyzed, 4 showed gains and losses consistent with malignant melanoma. None of these 4 patients had any clinical evidence of malignancy during a mean follow-up period of 3.5 years (range, years). One MLUMP displayed malignant behavior in the form of a positive SLN. This clinically malignant MLUMP had an SNP-GMA pattern consistent with a benign nevus (Figure 6, A through C). This patient was lost to followup immediately after the positive SLN diagnosis. COMMENT This SNP-based molecular inversion probe GMA is a sensitive and highly specific method for detecting melanoma (89% sensitivity, 100% specificity) in this cohort of cases with a definitive histologic diagnosis. This SNP-GMA platform s performance in predicting the malignant potential of cases with an ambiguous histologic diagnosis was less impressive, identifying the 1 MLUMP with malignant clinical behavior (a positive Arch Pathol Lab Med Vol 136, August 2012 Melanoma Microarray Chandler et al 949
4 Figure 2. Genome-wide view of probe signal intensity of a malignant melanoma from the arm of a 36-year-old man. The patient died of metastatic melanoma 3 years later. Note the abrupt gains and losses of chromosomal material, characteristic of malignant melanoma (upper plot). The gains and losses correlate well with the dominant allele frequency plot (lower plot), adding further confidence to the copy number calls. The y-axis of the upper plot is the number of copies, with normal diploid (2 copies) normalized to 0. The y-axis of the lower plot is dominant allele frequency, with.5 representing a heterozygous state and 1 representing a homozygous state. The x-axis is the chromosome number. Figure 3. Genome-wide view of probe signal intensity that consensus determined to be equivocal possibly representing malignant melanoma, possibly representing a benign nevus. Note the subtle copy number decline in 6q and all of chromosome 9. This is a sample of a malignant melanoma from the cheek of a 26-year-old woman who has had no further evidence of disease with 6 years of follow-up. If the subtle copy number changes are real, the low amplitude could have resulted from dilution of the undissected tumor sample with a large quantity of normal-tissue DNA, or alternatively, only a small percentage of tumor cells may have contained the chromosomal copy number aberrations. The y-axis of the upper plot is the number of copies, with normal diploid (2 copies) normalized to 0. The y-axis of the lower plot is dominant allele frequency, with.5 representing a heterozygous state and 1 representing a homozygous state. The x-axis is the chromosome number. 950 Arch Pathol Lab Med Vol 136, August 2012 Melanoma Microarray Chandler et al
5 Figure 4. Low-power image of the malignant melanoma from the cheek of a 26-year-old woman shown in Figure 3. Note the large amount of normal tissue (epidermis, dermis, and adnexa). This melanoma is nevoid and may be arising in a preexisting nevus (hematoxylin-eosin, original magnification 320). SLN) as a benign nevus and 4 MLUMPs with no further evidence of disease during follow-up as having a genomic pattern similar to that observed in malignant melanoma. A limitation of this study is the relatively short clinical follow-up period (median, 3.1 years) for the 4 MLUMPs with an SNP-GMA pattern consistent with melanoma. It is possible that some of these lesions will eventually display clinically malignant behavior. It is also possible that these types of lesions have a low malignant potential that is effectively treated by narrow excision, or that these lesions have no malignant potential but still possess genomic changes that resemble melanoma as does their histology. In addition to demonstrating this platform s ability to differentiate malignant melanoma from benign nevi, this study has accomplished a significant technologic achievement by forgoing microdissection of the paraffin block before microarray analysis of selected clinical biopsy specimens. Figures 7 and 8 show that 3 copies of chromosome 2, present in approximately 20% of the amplified sample, can be clearly differentiated from the adjacent chromosome 1q with a normal copy number of 2.14 This finding implies that a chromosomal gain or loss present in as few as 20% of the biopsy cells can be detected against a normal background. Rigorous dilution studies should be performed for confirmation. If these findings are upheld, microdissection would be unnecessary for many compound melanocytic lesions, but would still be required for most junctional melanocytic proliferations or lesions with a dense inflammatory infiltrate. Removing the nonautomatable step of microdissection streamlines the process of SNP-GMA, making it simpler and even more practical for research and diagnostic purposes. A second major technical accomplishment of this study is the demonstration that a very small quantity of DNA can provide high-quality SNP-GMA results for melanocytic lesions. Using the OncoScan FFPE Express Array, we were able to detect clear gains and losses consistent with the diagnosis of melanoma from a shave biopsy from which we extracted 50 ng of DNA (Figure 9). The current recommended specimen requirement for the Agilent 180K Figure 5. Genome-wide view of probe signal intensity for a case of malignant melanoma from the arm of an 85-year-old woman. The upper plot shows chromosome 9 to be copy number neutral (diploid). The lower plot reveals a loss of heterozygosity involving the majority of the short arm of chromosome 9. In sum, this is a copy number neutral loss of heterozygosity. Also of note, the copy number changes detected in this malignant melanoma did not involve regions targeted by the melanoma fluorescent in situ hybridization assay. The y-axis of the upper plot is the number of copies, with normal diploid (2 copies) normalized to 0. The y-axis of the lower plot is dominant allele frequency, with.5 representing a heterozygous state and 1 representing a homozygous state. The x-axis is the chromosome number. Arch Pathol Lab Med Vol 136, August 2012 Melanoma Microarray Chandler et al 951
6 Figure 6. A, Low-power view of the melanocytic lesion of uncertain malignant potential (MLUMP) from a 19-year-old who developed a positive sentinel lymph node (SLN). B, Higher-power view of the MLUMP lesion from a 19-year-old who developed a positive SLN. C, Genome-wide view of probe signal intensity for the primary MLUMP lesion from a 19-year-old who developed a positive SLN. There are no significant gains or losses of chromosomal material or loss of heterozygosity, making it indistinguishable from a benign melanocytic nevus. The y-axis of the upper plot is the number of copies, with normal diploid (2 copies) normalized to 0. The y-axis of the lower plot is dominant allele frequency, with.5 representing a heterozygous state and 1 representing a homozygous state. The x-axis is the chromosome number (hematoxylin-eosin, original magnifications 320 [A] and 3200 [B]). microarray testing for melanoma at University of California San Francisco is 500 ng. Therefore, with this novel Affymetrix platform, SNP-GMA testing could become an ancillary diagnostic option for even smaller FFPE biopsy specimens. Recently, fluorescence in situ hybridization (FISH) has been developed as an ancillary molecular test for malignant melanoma. The benefit of FISH testing is that it requires less tissue for analysis (about 30 malignant cells)9 than standard genomic array technology and can 952 Arch Pathol Lab Med Vol 136, August 2012 be used effectively without microdissection in situations where a relatively small melanocytic population is surrounded by an abundance of normal cells.8 We expect FISH testing to remain an effective diagnostic tool for the differentiation of nodal nevus versus melanoma metastatic to a lymph node and for benign proliferative nodule versus melanoma developing in a large nevus. However, our study has effectively dropped the minimum specimen requirement by a factor of 10, from 500 to 50 ng of DNA, making microdissection coupled with Melanoma Microarray Chandler et al
7 Figure 7. Genome-wide view of probe signal intensity for a case of malignant melanoma from the neck of a 71-year-old woman. Notably, there are no copy number changes detected in regions targeted by the melanoma fluorescent in situ hybridization panel. The y-axis of the upper plot is the number of copies, with normal diploid (2 copies) normalized to 0. The y-axis of the lower plot is dominant allele frequency, with.5 representing a heterozygous state and 1 representing a homozygous state. The x-axis is the chromosome number. SNP-GMA analysis a viable option for some of these lesions. A major advantage of SNP-GMA compared with FISH is the breadth and quantifiable detail of the results. A commercially available FISH panel for the diagnosis of melanoma contains 4 probes directed against 2 chromosomes Figure 8. Closer view of chromosomes 1 and 2 from Figure 7. Mean signal intensity (y-axis intercept) can be used to estimate the percentage of cells in the sample harboring the gain or loss of chromosomal material. The yellow bracket (1q) shows a region where the mean signal intensity (indicated by the horizontal black line) is 0, which has been normalized to correspond to 2 copies. The red bracket (2) indicates a region where the mean signal intensity (y-axis intercept of the horizontal black line) is approximately.20. This reveals that approximately 20% of the cells have 3 copies of chromosome 2. If 50% of the cells had 3 copies, the y intercept would be.5 and if 100% had 3 copies the intercept would be 1.0. The significance of the nominal y-intercept value is clearly visible for the X chromosome in our male samples (Figures 2 and 10) where the y- intercept is approximately 21.0, essentially a copy number loss to 1 copy (normal male). (6p25 RREB1, 6q23 MYB, 6centromere, 11q13 CCND1). This FISH panel was first described by Gerami et al 9 in 2009 with an 86.7% sensitivity, and later with a 77% sensitivity after further testing and development by NeoGenomics. 15 A flurry of recent publications has demonstrated excellent sensitivity of FISH for a number of melanoma subtypes, with desmoplastic melanoma being the exception However, a small study recently suggested that the sensitivity of this FISH panel for the detection of melanocytic lesions that will have a malignant clinical behavior is much lower at 60%. 21 Our results suggest that this FISH panel would have missed 6 melanomas in our cohort that SNP-GMA detected, one of which proved to be lethal to the patient (Figures 10 and 11). This assumed sensitivity is based upon the fact that we did not detect gains or losses in the regions targeted by the FISH probes or the copy number changes the probes were designed to detect (loss versus gain). It is possible that gains or losses could have been detected in a subpopulation if they were actually analyzed by FISH. These 6 melanomas detected by SNP-GMA that we expect would have been missed by the FISH panel all had a gain or loss that involved a portion of either chromosome 7, 8, or 9. The original work of Bastian et al 6,7 described changes to these chromosomes as some of the most common in malignant melanoma. The wealth and specificity of information available from an SNP-GMA will make this technology cost-effective as mutation-specific therapies for malignant melanoma become standard. Although the SNP-GMA used in this study was not optimized for melanoma, the modularity of the molecular inversion probe design means clinically relevant SNPs such as the BRAF V600E could potentially be included as one of the SNPs detected. In fact, the most recent version of the OncoScan FFPE Express from Affymetrix (version 2.0, released May 2011) has been designed and optimized to detect the BRAF V600E and Arch Pathol Lab Med Vol 136, August 2012 Melanoma Microarray Chandler et al 953
8 Figure 9. Genome-wide view of probe signal intensity for a case of malignant melanoma from the leg of a 79-year-old woman. This sample yielded 50 ng of DNA. Though there is variability in probe signal intensity in the upper plot, losses consistent with melanoma (3q, 8p, 9 and 10) can be seen and are confirmed in the lower dominant allele frequency plot. The y-axis of the upper plot is the number of copies, with normal diploid (2 copies) normalized to 0. The y-axis of the lower plot is dominant allele frequency, with.5 representing a heterozygous state and 1 representing a homozygous state. The x-axis is the chromosome number. other somatic mutations. This implies a single SNP-GMA test could be used to confirm the diagnosis of malignant melanoma, stratify the risk of recurrence, and direct pharmacologic interventions. Although the sensitivity and specificity of SNP-GMA for detecting malignant melanoma is good, our small series highlights one case where the failure of SNP-GMA is concerning. This case involved the only histologically ambiguous melanocytic lesion that had a malignant clinical course, in the form of a positive SLN (Figure 6). The patient had no additional clinical follow-up at our facility following a positive SLN biopsy, so additional outcome data are not available. The possibility that the melanocytes in the SLN represent a nodal nevus or benign Figure 10. Genome-wide view of probe signal intensity for a case of malignant melanoma from the scalp of a 73-year-old man. The patient died of metastatic disease 2.5 years later. We did not detect gains or losses of genomic material that would have resulted in a diagnosis of malignant melanoma by the commercially available fluorescence in situ hybridization (FISH) panel for melanoma. Although there is some loss of chromosome 11, the 11q13 melanoma FISH probe is designed to detect amplifications and therefore may not have identified this copy number alteration as abnormal. The y-axis of the upper plot is the number of copies, with normal diploid (2 copies) normalized to 0. The y-axis of the lower plot is dominant allele frequency, with.5 representing a heterozygous state and 1 representing a homozygous state. The x-axis is the chromosome number. 954 Arch Pathol Lab Med Vol 136, August 2012 Melanoma Microarray Chandler et al
9 Figure 11. Focused view of the region of loss in 6q demonstrates that the 6q23 fluorescent in situ hybridization probe for MYB (vertical red line) is more than 10 megabases distant and would therefore not be expected to register the loss. metastasizing nevus is small, given the histologic findings, which included a mitotic figure in the parenchymal nodal metastasis and the patient s postpubertal age of 19 years. It is possible that the false-negative SNP-GMA result occurred because of a small malignant clone that metastasized early, but was below our threshold of detection in the primary lesion. It is also possible that this melanoma developed the ability to metastasize through point mutations or translocations that did not result in gains or losses of chromosomal material and were therefore undetectable by our SNP-GMA. A final possibility is a technical failure in the performance of the assay, as we were unable to perform repeat testing on this sample. In summary, we have demonstrated that an SNP-GMA can detect gains and losses and loss of heterozygosity of chromosomal material characteristic of malignant melanoma in archived FFPE biopsy specimens with as little as 50 ng of DNA. The sensitivity of melanoma detection was good in the entire study sample (including both histologically malignant and ambiguous lesions with malignant clinical behavior) at 86% (n 5 24 of 28). The sensitivity for detecting melanomas with an aggressive clinical course (positive SLN and/or metastatic disease) was similar at 82% (n 5 9 of 11). Our results show that SNP-based GMA will have a role in the diagnosis and potentially in the risk stratification and treatment of malignant melanoma. This study was supported by a $ Resident Research Support Grant from the University of Utah Department of Pathology (Dr Chandler) and $ in University of Utah ARUP Laboratories Research and Development Funds (Dr South). References 1. National Cancer Institute. SEER stat fact sheets: melanoma of the skin. seer.cancer.gov/statfacts/html/melan.html. Accessed March 15, Corona R, Mele A, Amini M, et al. Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions. J Clin Oncol. 1996;14(4): Farmer ER, Gonin R, Hanna MP. Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists. Hum Pathol. 1996;27(6): Lodha S, Saggar S, Celebi JT, Silvers DN. Discordance in the histopathologic diagnosis of difficult melanocytic neoplasms in the clinical setting. J Cutan Pathol. 2008;35(4): Shoo BA, Sagebiel RW, Kashani-Sabet M. Discordance in the histopathologic diagnosis of melanoma at a melanoma referral center. J Am Acad Dermatol. 2010;62(5): Bastian BC, LeBoit PE, Hamm H, Brocker EB, Pinkel D. Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization. Cancer Res. 1998;58(10): Bastian BC, Olshen AB, LeBoit PE, Pinkel D. Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol. 2003;163(5): Dalton SR, Gerami P, Kolaitis NA, et al. Use of fluorescence in situ hybridization (FISH) to distinguish intranodal nevus from metastatic melanoma. Am J Surg Pathol. 2010;34(2): Gerami P, Jewell SS, Morrison LE, et al. Fluorescence in situ hybridization (FISH) as an ancillary diagnostic tool in the diagnosis of melanoma. Am J Surg Pathol. 2009;33(8): Affymetrix. Oncoscan FFPE express services. estore/browse/products.jsp?productid5prod150008#1_1. Accessed March 15, Wang Y, Carlton VE, Karlin-Neumann G, et al. High quality copy number and genotype data from FFPE samples using molecular inversion probe (MIP) microarrays. BMC Med Genomics. 2009;2: Wang Y, Moorhead M, Karlin-Neumann G, et al. Allele quantification using molecular inversion probes (MIP). Nucleic Acids Res. 2005;33(21):e Wang Y, Moorhead M, Karlin-Neumann G, et al. Analysis of molecular inversion probe performance for allele copy number determination. Genome Biol. 2007;8(11):R Nancarrow DJ, Handoko HY, Stark MS, Whiteman DC, Hayward NK. SiDCoN: a tool to aid scoring of DNA copy number changes in SNP chip data. PLoS One. 2007;2(10):e Gasparini R. A new FISH test for melanoma. Paper presented at: 35th Annual Association of Genetic Technologists Meeting; June 3 5, 2010; Phoenix, AZ. 16. Gammon B, Beilfuss B, Guitart J, Busam KJ, Gerami P. Fluorescence in situ hybridization for distinguishing cellular blue nevi from blue nevus-like melanoma. J Cutan Pathol. 2011;38(4): Gerami P, Beilfuss B, Haghighat Z, Fang Y, Jhanwar S, Busam KJ. Fluorescence in situ hybridization as an ancillary method for the distinction of desmoplastic melanomas from sclerosing melanocytic nevi. J Cutan Pathol. 2011; 38(4): Gerami P, Mafee M, Lurtsbarapa T, Guitart J, Haghighat Z, Newman M. Sensitivity of fluorescence in situ hybridization for melanoma diagnosis using RREB1, MYB, Cep6, and 11q13 probes in melanoma subtypes. Arch Dermatol. 2010;146(3): Gerami P, Wass A, Mafee M, Fang Y, Pulitzer MP, Busam KJ. Fluorescence in situ hybridization for distinguishing nevoid melanomas from mitotically active nevi. Am J Surg Pathol. 2009;33(12): Pouryazdanparast P, Newman M, Mafee M, Haghighat Z, Guitart J, Gerami P. Distinguishing epithelioid blue nevus from blue nevus-like cutaneous melanoma metastasis using fluorescence in situ hybridization. Am J Surg Pathol. 2009;33(12): Gaiser T, Kutzner H, Palmedo G, et al. Classifying ambiguous melanocytic lesions with FISH and correlation with clinical long-term follow up. Mod Pathol. 2010;23(3): Arch Pathol Lab Med Vol 136, August 2012 Melanoma Microarray Chandler et al 955
Page 1 of 3. We suggest the following changes:
Page 1 of 3 Loren E. Clarke, M.D. Myriad Genetic Laboratories, Inc. 320 Wakara Way, Salt Lake City, UT 84108 Phone: 801.883.3470 Email: lclarke@myriad.com Date of Request: June 2017 NCCN Guidelines Panel:
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