A Novel Scoring System for MYB RNA In Situ Hybridization Displays High Sensitivity and Specificity for Adenoid Cystic Carcinoma in a Clinical Setting.
Humans
Carcinoma, Adenoid Cystic
/ diagnosis
Proto-Oncogene Proteins c-myb
/ genetics
Female
Sensitivity and Specificity
Middle Aged
Male
Aged
Adult
Biomarkers, Tumor
/ analysis
Retrospective Studies
In Situ Hybridization
/ methods
Prospective Studies
Aged, 80 and over
In Situ Hybridization, Fluorescence
/ methods
Young Adult
Myb gene
Adenoid cystic carcinoma
Hybridization
In situ
Logistic regression
Quantitative scoring
Salivary gland neoplasms
mRNA
Journal
Head and neck pathology
ISSN: 1936-0568
Titre abrégé: Head Neck Pathol
Pays: United States
ID NLM: 101304010
Informations de publication
Date de publication:
19 Jun 2024
19 Jun 2024
Historique:
received:
05
05
2024
accepted:
21
05
2024
medline:
19
6
2024
pubmed:
19
6
2024
entrez:
19
6
2024
Statut:
epublish
Résumé
MYB RNA in situ hybridization (ISH) has emerged as a reliable and accessible marker to support adenoid cystic carcinoma (ACC) diagnosis, though still not well studied. Here, we report our results in a validation and prospective cohort to improve MYB RNA ISH diagnostic accuracy. 79 cases (23 retrospective and 56 prospective) underwent MYB RNA ISH testing (44 ACC and 35 non-ACC). MYB RNA ISH results were initially interpreted based on previously established (original) scoring criteria. Weighted "i-scores", percent positive tumor cells, percent tumor cells with large signals (% LS), and staining pattern (abluminal, diffuse, focal non-patterned, or negative) were inputs for logistic regression models. Final model performance characteristics were compared with original scoring criteria and MYB::NFIB FISH results. An abluminal pattern was characteristic and exclusive to ACC. All i-scores, % LS, and percent positive were significantly higher in ACC. Original scoring criteria yielded a 95.5% sensitivity (Sn), 68.6% specificity (Sp), and 83.5% accuracy. MYB::NFIB FISH yielded a 42.9% sensitivity, 100% specificity, and 60% accuracy. Optimizing for performance, simplicity, and minimal collinearity, our final model was defined as: abluminal pattern and/or % LS > 16.5%, which resulted in a 93.2% Sn, 97.1% Sp, and 94.9% accuracy for ACC diagnosis. False negatives included an ACC with striking tubular eosinophilia and a MYBL1::NFIB translocated ACC. One false positive exclusive to the final model was a nasopharyngeal carcinoma with MYB amplification. MYB RNA ISH has a higher Sn than MYB::NFIB FISH while retaining high Sp. Our model provides improvements to specificity compared to original scoring criteria and highlight the importance of abluminal staining pattern and % LS. Nonetheless, alternate fusions remain key false negatives while rare non-ACC with other mechanisms of MYB activation may present as false positives.
Sections du résumé
BACKGROUND
BACKGROUND
MYB RNA in situ hybridization (ISH) has emerged as a reliable and accessible marker to support adenoid cystic carcinoma (ACC) diagnosis, though still not well studied. Here, we report our results in a validation and prospective cohort to improve MYB RNA ISH diagnostic accuracy.
METHODS
METHODS
79 cases (23 retrospective and 56 prospective) underwent MYB RNA ISH testing (44 ACC and 35 non-ACC). MYB RNA ISH results were initially interpreted based on previously established (original) scoring criteria. Weighted "i-scores", percent positive tumor cells, percent tumor cells with large signals (% LS), and staining pattern (abluminal, diffuse, focal non-patterned, or negative) were inputs for logistic regression models. Final model performance characteristics were compared with original scoring criteria and MYB::NFIB FISH results.
RESULTS
RESULTS
An abluminal pattern was characteristic and exclusive to ACC. All i-scores, % LS, and percent positive were significantly higher in ACC. Original scoring criteria yielded a 95.5% sensitivity (Sn), 68.6% specificity (Sp), and 83.5% accuracy. MYB::NFIB FISH yielded a 42.9% sensitivity, 100% specificity, and 60% accuracy. Optimizing for performance, simplicity, and minimal collinearity, our final model was defined as: abluminal pattern and/or % LS > 16.5%, which resulted in a 93.2% Sn, 97.1% Sp, and 94.9% accuracy for ACC diagnosis. False negatives included an ACC with striking tubular eosinophilia and a MYBL1::NFIB translocated ACC. One false positive exclusive to the final model was a nasopharyngeal carcinoma with MYB amplification.
CONCLUSIONS
CONCLUSIONS
MYB RNA ISH has a higher Sn than MYB::NFIB FISH while retaining high Sp. Our model provides improvements to specificity compared to original scoring criteria and highlight the importance of abluminal staining pattern and % LS. Nonetheless, alternate fusions remain key false negatives while rare non-ACC with other mechanisms of MYB activation may present as false positives.
Identifiants
pubmed: 38896376
doi: 10.1007/s12105-024-01656-z
pii: 10.1007/s12105-024-01656-z
doi:
Substances chimiques
Proto-Oncogene Proteins c-myb
0
MYB protein, human
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
51Subventions
Organisme : Clinical and Translational Sciences Institute at the University of Pittsburgh
ID : Grant Number UL1-TR-001857
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Saleh E, Ukwas A (2023) Adenoid cystic carcinoma of salivary glands: a 10-year review and an assessment of the current management, surgery, radiotherapy, and chemotherapy. Int J Otolaryngol 2023:7401458
doi: 10.1155/2023/7401458
Robin C, Laboulbène JA (1853) Memoire sur trois productions morbides non decrites. Compte Rend Soc Biol 5:185–196
Seethala RR et al (2007) Adenoid cystic carcinoma with high-grade transformation: a report of 11 cases and a review of the literature. Am J Surg Pathol 31(11):1683–1694
doi: 10.1097/PAS.0b013e3180dc928c
Seethala RR (2017) Basaloid/blue salivary gland tumors. Mod Pathol 30(s1):S84-s95
doi: 10.1038/modpathol.2016.190
Khan AJ et al (2001) Adenoid cystic carcinoma: a retrospective clinical review. Int J Cancer 96(3):149–158
doi: 10.1002/ijc.1013
Conley J, Dingman DL (1974) Adenoid cystic carcinoma in the head and neck (cylindroma). Arch Otolaryngol 100(2):81–90
doi: 10.1001/archotol.1974.00780040087001
Jones AS et al (1997) Adenoid cystic carcinoma of the head and neck. Clin Otolaryngol Allied Sci 22(5):434–443
doi: 10.1046/j.1365-2273.1997.00041.x
Spiro RH, Huvos AG (1992) Stage means more than grade in adenoid cystic carcinoma. Am J Surg 164(6):623–628
doi: 10.1016/S0002-9610(05)80721-4
Stell PM et al (1985) Adenoid cystic carcinoma: the results of radical surgery. Clin Otolaryngol Allied Sci 10(4):205–208
doi: 10.1111/j.1365-2273.1985.tb00242.x
McDermott J et al (2015) Local therapy for metastatic salivary adenoid cystic carcinoma: a surveillance, epidermiology, and end results and national cancer data base analysis. Int J Radiat Oncol Biol phys 94(4):953
doi: 10.1016/j.ijrobp.2015.12.301
Mino M, Pilch BZ, Faquin WC (2003) Expression of KIT (CD117) in neoplasms of the head and neck: an ancillary marker for adenoid cystic carcinoma. Mod Pathol 16(12):1224–1231
doi: 10.1097/01.MP.0000096046.42833.C7
Penner CR, Folpe AL, Budnick SD (2002) C-kit expression distinguishes salivary gland adenoid cystic carcinoma from polymorphous low-grade adenocarcinoma. Mod Pathol 15(7):687–691
doi: 10.1097/01.MP.0000018973.17736.F8
Vila L et al (2009) Identification of c-kit gene mutations in primary adenoid cystic carcinoma of the salivary gland. Mod Pathol 22(10):1296–1302
doi: 10.1038/modpathol.2009.95
Nordkvist A et al (1994) Non-random chromosome rearrangements in adenoid cystic carcinoma of the salivary glands. Genes Chromosomes Cancer 10(2):115–121
doi: 10.1002/gcc.2870100206
Persson M et al (2009) Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proc Natl Acad Sci U S A 106(44):18740–18744
doi: 10.1073/pnas.0909114106
Brayer KJ et al (2016) Recurrent fusions in MYB and MYBL1 define a common, transcription factor-driven oncogenic pathway in salivary gland adenoid cystic carcinoma. Cancer Discov 6(2):176–187
doi: 10.1158/2159-8290.CD-15-0859
Fehr A et al (2011) The MYB-NFIB gene fusion-a novel genetic link between adenoid cystic carcinoma and dermal cylindroma. J Pathol 224(3):322–327
doi: 10.1002/path.2909
Weinreb I et al (2023) Adenoid cystic carcinoma with striking tubular hypereosinophilia: a unique pattern associated with nonparotid location and both canonical and novel EWSR1::MYB and FUS::MYB Fusions. Am J Surg Pathol 47(4):497–503
doi: 10.1097/PAS.0000000000002023
Gao R et al (2014) A unifying gene signature for adenoid cystic cancer identifies parallel MYB-dependent and MYB-independent therapeutic targets. Oncotarget 5(24):12528–12542
doi: 10.18632/oncotarget.2985
Mitani Y et al (2010) Comprehensive analysis of the MYB-NFIB gene fusion in salivary adenoid cystic carcinoma: incidence, variability, and clinicopathologic significance. Clin Cancer Res 16(19):4722–4731
doi: 10.1158/1078-0432.CCR-10-0463
Brill LB 2nd et al (2011) Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms. Mod Pathol 24(9):1169–1176
doi: 10.1038/modpathol.2011.86
Rooney SL, Robinson RA (2017) Immunohistochemical expression of MYB in salivary gland basal cell adenocarcinoma and basal cell adenoma. J Oral Pathol Med 46(9):798–802
doi: 10.1111/jop.12617
Pusztaszeri MP et al (2014) MYB immunostaining is a useful ancillary test for distinguishing adenoid cystic carcinoma from pleomorphic adenoma in fine-needle aspiration biopsy specimens. Cancer Cytopathol 122(4):257–265
doi: 10.1002/cncy.21381
Rooper LM et al (2021) MYB RNA in situ hybridization facilitates sensitive and specific diagnosis of adenoid cystic carcinoma regardless of translocation status. Am J Surg Pathol 45(4):488–497
doi: 10.1097/PAS.0000000000001616
Butcher MR et al (2022) MYB RNA in situ hybridization is a useful diagnostic tool to distinguish breast adenoid cystic carcinoma from other triple-negative breast carcinomas. Am J Surg Pathol 46(7):878–888
doi: 10.1097/PAS.0000000000001913
McClelland RA et al (1990) Automated quantitation of immunocytochemically localized estrogen receptors in human breast cancer. Cancer Res 50(12):3545–3550
Wickham H (2016) ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag, New York
doi: 10.1007/978-3-319-24277-4
Robin X et al (2011) pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 12:77
doi: 10.1186/1471-2105-12-77
Kosmidis I et al (2023) Mean and median bias reduction in generalized linear models. Stat Computing 30:43–59
doi: 10.1007/s11222-019-09860-6
Long, J., jtools: Analysis and Presentation of Social Scientific Data. 2022.
Friedman J et al (2010) Regularization paths for generalized linear models viacoordinate descent. J Stat Softw 33:1–22
doi: 10.18637/jss.v033.i01
Tadi S et al (2023) MYB RNA detection by in situ hybridisation has high sensitivity and specificity for the diagnosis of adenoid cystic carcinoma. Pathology 55(4):456–465
doi: 10.1016/j.pathol.2023.01.007
Ueda K et al (2023) The landscape of MYB/MYBL1-and Peri-MYB/MYBL1-associated rearrangements in adenoid cystic carcinoma. Mod Pathol 36(10):100274
doi: 10.1016/j.modpat.2023.100274
Yadav U et al (2023) Diagnosis of adenoid cystic carcinoma with striking tubular hypereosinophilia by MYB and EWSR1 breakapart fluorescence in situ hybridization. Head Neck Pathol 17(4):940–951
doi: 10.1007/s12105-023-01596-0
Ferrarotto R et al (2017) Activating NOTCH1 mutations define a distinct subgroup of patients with adenoid cystic carcinoma who have poor prognosis, propensity to bone and liver metastasis, and potential responsiveness to Notch1 inhibitors. J Clin Oncol 35(3):352–360
doi: 10.1200/JCO.2016.67.5264
Sajed DP et al (2017) Diffuse staining for activated NOTCH1 correlates with NOTCH1 mutation status and is associated with worse outcome in adenoid cystic carcinoma. Am J Surg Pathol 41(11):1473–1482
doi: 10.1097/PAS.0000000000000945
Zhou MJ et al (2023) Increased retinoic acid signaling decreases lung metastasis in salivary adenoid cystic carcinoma by inhibiting the noncanonical Notch1 pathway. Exp Mol Med 55(3):597–611
doi: 10.1038/s12276-023-00957-7
Ferrarotto R et al (2022) AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling. Cell Death Dis 13(8):678
doi: 10.1038/s41419-022-05133-9
Andersson MK, Åman P, Stenman G (2019) IGF2/IGF1R signaling as a therapeutic target in MYB-positive adenoid cystic carcinomas and other fusion gene-driven tumors. Cells. https://doi.org/10.3390/cells8080913
doi: 10.3390/cells8080913
Persson M et al (2012) Clinically significant copy number alterations and complex rearrangements of MYB and NFIB in head and neck adenoid cystic carcinoma. Genes Chromosomes Cancer 51(8):805–817
doi: 10.1002/gcc.21965