Top

Published in:

Open Access 01-11-2021 | Original Article

Mucoepidermoid carcinoma of the salivary glands revisited with special reference to histologic grading and CRTC1/3-MAML2 genotyping

Authors: André Fehr, Sarah Werenicz, Pietro Trocchi, Markus Falk, Reinhard E. Friedrich, Angelika Stammler, Andreas Stang, Florian Oesterling, Laura Khil, Göran Stenman, Werner Böcker, Katharina Tiemann, Thomas Löning

Published in: Virchows Archiv | Issue 5/2021

Abstract

Mucoepidermoid carcinoma (MEC) is the most common carcinoma of the salivary glands. Here, we have used two large patient cohorts with MECs comprising 551 tumors to study clinical, histological, and molecular predictors of survival. One cohort (n = 167), with known CRCT1/3-MAML2 fusion status, was derived from the Hamburg Reference Centre (HRC; graded with the AFIP and Brandwein systems) and the other (n = 384) was derived from the population-based Cancer Registry of North Rhine-Westphalia (LKR-NRW; graded with the AFIP system). The reliability of both the AFIP and Brandwein grading systems was excellent (n = 155). The weighted kappa for inter-rater agreement was 0.81 (95% CI 0.65–0.97) and 0.83 (95% CI 0.71–0.96) for the AFIP and Brandwein systems, respectively. The 5-year relative survival was 79.7% (95% CI 73.2–86.2%). Although the Brandwein system resulted in a higher rate of G3-MECs, survival in G3-tumors (AFIP or Brandwein grading) was markedly worse than in G1/G2-tumors. Survival in > T2 tumors was markedly worse than in those with lower T-stage. Also, fusion-negative MECs had a worse 5-year progression-free survival. The frequency of fusion-positive MECs in the HRC cohort was 78.4%, of which the majority (86.7%) was G1/G2-tumors. In conclusion, the AFIP and Brandwein systems are useful in estimating prognosis and to guide therapy for G3-MECs. However, their significance regarding young age (≤ 30 years) and location-dependent heterogeneity of in particular G2-tumors is more questionable. We conclude that CRTC1/3-MAML2 testing is a useful adjunct to histologic scoring of MECs and for pinpointing tumors with poor prognosis with higher precision, thus avoiding overtreatment.

Available only for authorised users

Locati LD, Collini P, Imbimbo M, Barisella M, Testi A, Licitra LF, Loning T, Tiemann K, Quattrone P, Bimbatti E, Chiaravalli S, Casanova M, Tamborini E, Carta R, Gasparini P, Guzzo M, Massimino M, Ferrari A (2017) Immunohistochemical and molecular profile of salivary gland cancer in children. Pediatr Blood Cancer 64(9). https://doi.org/10.1002/pbc.26468

El-Naggar AK, Grandis JR, Slootweg PJ, Chan JKC, Takata T (2017) WHO Classification of Tumours of the Head and Neck. WHO/IARC Classification of Tumours of the Head and Neck, 4th edn. Lyon: IARC Press

Kleinsasser O (1969) Mucoepidermoid tumors of salivary glands. Arch Klin Exp Ohren Nasen Kehlkopfheilkd 193(2):171–189. https://doi.org/10.1007/BF00401704CrossRefPubMed

Seifert G (1972) The epithelial tumors of the salivary glands. Fortschr Kiefer Gesichtschir 15:2–18PubMed

Seifert G, Sobin LH (1991) Histological typing of salivary gland tumours. World Health Organization. International histological classification of tumours, 2nd edition edn. Berlin-Heidelberg-New York: Springer. https://doi.org/10.1007/978-3-642-84506-2

Goode RK, Auclair PL, Ellis GL (1998) Mucoepidermoid carcinoma of the major salivary glands: clinical and histopathologic analysis of 234 cases with evaluation of grading criteria. Cancer 82(7):1217–1224CrossRef

Auclair PL, Goode RK, Ellis GL (1992) Mucoepidermoid carcinoma of intraoral salivary glands evaluation and application of grading criteria in 143 cases. Cancer 69(8):2021–2030CrossRef

Stenman G, Persson F, Andersson MK (2014) Diagnostic and therapeutic implications of new molecular biomarkers in salivary gland cancers. Oral Oncol 50(8):683–690. https://doi.org/10.1016/j.oraloncology.2014.04.008CrossRefPubMed

Brandwein MS, Ivanov K, Wallace DI, Hille JJ, Wang B, Fahmy A, Bodian C, Urken ML, Gnepp DR, Huvos A, Lumerman H, Mills SE (2001) Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol 25(7):835–845. https://doi.org/10.1097/00000478-200107000-00001CrossRefPubMed

10.

Ellis G, Auclair P (1996) Tumors of the salivary glands. In: Atlas of tumor pathology. vol 3rd. Washington DC: Armed Forces Institute of Pathology

11.

Skalova A, Stenman G, Simpson RHW, Hellquist H, Slouka D, Svoboda T, Bishop JA, Hunt JL, Nibu KI, Rinaldo A, Vander Poorten V, Devaney KO, Steiner P, Ferlito A (2018) The role of molecular testing in the differential diagnosis of salivary gland carcinomas. Am J Surg Pathol 42(2):e11–e27. https://doi.org/10.1097/PAS.0000000000000980CrossRefPubMed

12.

Nordkvist A, Gustafsson H, Juberg-Ode M, Stenman G (1994) Recurrent rearrangements of 11q14-22 in mucoepidermoid carcinoma. Cancer Genet Cytogenet 74(2):77–83. https://doi.org/10.1016/0165-4608(94)90001-9CrossRefPubMed

13.

Enlund F, Behboudi A, Andren Y, Oberg C, Lendahl U, Mark J, Stenman G (2004) Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin’s tumors. Exp Cell Res 292(1):21–28. https://doi.org/10.1016/j.yexcr.2003.09.007CrossRefPubMed

14.

Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T, O’Neil K, Stover K, El-Naggar A, Griffin JD, Kirsch IR, Kaye FJ (2003) t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 33(2):208–213. https://doi.org/10.1038/ng1083CrossRefPubMed

15.

Behboudi A, Enlund F, Winnes M, Andren Y, Nordkvist A, Leivo I, Flaberg E, Szekely L, Makitie A, Grenman R, Mark J, Stenman G (2006) Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene. Genes Chromosomes Cancer 45(5):470–481. https://doi.org/10.1002/gcc.20306CrossRefPubMed

16.

Fehr A, Meyer A, Heidorn K, Röser K, Löning T, Bullerdiek J (2009) A link between the expression of the stem cell marker HMGA2, grading, and the fusion CRTC1-MAML2 in mucoepidermoid carcinoma. Genes Chromosomes Cancer 48(9):777–785. https://doi.org/10.1002/gcc.20682CrossRefPubMed

17.

Jee KJ, Persson M, Heikinheimo K, Passador-Santos F, Aro K, Knuutila S, Odell EW, Makitie A, Sundelin K, Stenman G, Leivo I (2013) Genomic profiles and CRTC1-MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma. Mod Pathol 26(2):213–222. https://doi.org/10.1038/modpathol.2012.154CrossRefPubMed

18.

Fehr A, Roser K, Heidorn K, Hallas C, Loning T, Bullerdiek J (2008) A new type of MAML2 fusion in mucoepidermoid carcinoma. Genes Chromosomes Cancer 47(3):203–206. https://doi.org/10.1002/gcc.20522CrossRefPubMed

19.

Nakayama T, Miyabe S, Okabe M, Sakuma H, Ijichi K, Hasegawa Y, Nagatsuka H, Shimozato K, Inagaki H (2009) Clinicopathological significance of the CRTC3-MAML2 fusion transcript in mucoepidermoid carcinoma. Mod Pathol 22(12):1575–1581. https://doi.org/10.1038/modpathol.2009.126CrossRefPubMed

20.

Seethala RR, Dacic S, Cieply K, Kelly LM, Nikiforova MN (2010) A reappraisal of the MECT1/MAML2 translocation in salivary mucoepidermoid carcinomas. Am J Surg Pathol 34(8):1106–1121. https://doi.org/10.1097/PAS.0b013e3181de3021CrossRefPubMed

21.

Seethala RR, Chiosea SI (2016) MAML2 status in mucoepidermoid carcinoma can no longer be considered a prognostic marker. Am J Surg Pathol 40(8):1151–1153. https://doi.org/10.1097/PAS.0000000000000676CrossRefPubMed

22.

Koch-Institut R (2019) Krebs in Deutschland für 2015/2016. vol 12. Robert Koch Institut (Hrsg) und Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg); Berlin. https://doi.org/10.17886/rkipubl-2017-007

23.

Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley JD, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR (eds) (2017) AJCC Cancer Staging Manual, 8th edn. New York: Springer International Publishing

24.

Brenner H, Hakulinen T (2009) Up-to-date cancer survival: period analysis and beyond. Int J Cancer 124(6):1384–1390. https://doi.org/10.1002/ijc.24021CrossRefPubMed

25.

Brenner H, Gefeller O, Hakulinen T (2004) Period analysis for ‘up-to-date’ cancer survival data: theory, empirical evaluation, computational realisation and applications. Eur J Cancer 40(3):326–335. https://doi.org/10.1016/j.ejca.2003.10.013CrossRefPubMed

26.

Techavichit P, Hicks MJ, Lopez-Terrada DH, Quintanilla NM, Guillerman RP, Sarabia SF, Sayeed H, Nuchtern JG, Paulino AC, Muscal JA, Okcu MF, Chintagumpala M (2016) Mucoepidermoid carcinoma in children: a single institutional experience. Pediatr Blood Cancer 63(1):27–31. https://doi.org/10.1002/pbc.25681CrossRefPubMed

27.

Taylor ZC, Kaya EA, Bunn JD, Guss ZD, Mitchell BJ, Fairbanks RK, Lamoreaux WT, Wagner AE, Peressini BJ, Lee CM (2020) Overall and cause-specific survival for mucoepidermoid carcinoma of the major salivary glands: analysis of 2210 patients. World J Clin Oncol 11(12):1029–1044. https://doi.org/10.5306/wjco.v11.i12.1029CrossRefPubMedPubMedCentral

28.

Navale P, Rooper LM, Bishop JA, Westra WH (2019) Mucoepidermoid carcinoma of the oropharynx: a tumor type with a propensity for regional metastasis unrelated to histologic grade. Hum Pathol 93:1–5. https://doi.org/10.1016/j.humpath.2019.08.014CrossRefPubMed

29.

Seethala RR (2009) An update on grading of salivary gland carcinomas. Head Neck Pathol 3(1):69–77. https://doi.org/10.1007/s12105-009-0102-9CrossRefPubMedPubMedCentral

30.

Nance MA, Seethala RR, Wang Y, Chiosea SI, Myers EN, Johnson JT, Lai SY (2008) Treatment and survival outcomes based on histologic grading in patients with head and neck mucoepidermoid carcinoma. Cancer 113(8):2082–2089. https://doi.org/10.1002/cncr.23825CrossRefPubMed

31.

Cipriani NA, Lusardi JJ, McElherne J, Pearson AT, Olivas AD, Fitzpatrick C, Lingen MW, Blair EA (2019) Mucoepidermoid carcinoma: a comparison of histologic grading systems and relationship to MAML2 rearrangement and prognosis. Am J Surg Pathol 43(7):885–897. https://doi.org/10.1097/PAS.0000000000001252CrossRefPubMedPubMedCentral

32.

Okabe M, Miyabe S, Nagatsuka H, Terada A, Hanai N, Yokoi M, Shimozato K, Eimoto T, Nakamura S, Nagai N, Hasegawa Y, Inagaki H (2006) MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma. Clin Cancer Res 12(13):3902–3907. https://doi.org/10.1158/1078-0432.CCR-05-2376CrossRefPubMed

33.

Chan RC, Chan JY (2014) Head and neck mucoepidermoid carcinoma: a curious association with second primary malignancy. Otolaryngol Head Neck Surg 151(5):797–801. https://doi.org/10.1177/0194599814551131CrossRefPubMed

34.

Fonseca FP, de Andrade BA, Lopes MA, Pontes HA, Vargas PA, de Almeida OP (2013) P63 expression in papillary cystadenoma and mucoepidermoid carcinoma of minor salivary glands. Oral Surg Oral Med Oral Pathol Oral Radiol 115(1):79–86. https://doi.org/10.1016/j.oooo.2012.09.005CrossRefPubMed

35.

Lennerz JK, Perry A, Mills JC, Huettner PC, Pfeifer JD (2009) Mucoepidermoid carcinoma of the cervix: another tumor with the t(11;19)-associated CRTC1-MAML2 gene fusion. Am J Surg Pathol 33(6):835–843. https://doi.org/10.1097/PAS.0b013e318190cf5bCrossRefPubMed

36.

Wolfish EB, Nelson BL, Thompson LD (2012) Sinonasal tract mucoepidermoid carcinoma: a clinicopathologic and immunophenotypic study of 19 cases combined with a comprehensive review of the literature. Head Neck Pathol 6(2):191–207. https://doi.org/10.1007/s12105-011-0320-9CrossRefPubMed

37.

Fehr A, Roser K, Belge G, Loning T, Bullerdiek J (2008) A closer look at Warthin tumors and the t(11;19). Cancer Genet Cytogenet 180(2):135–139. https://doi.org/10.1016/j.cancergencyto.2007.10.007CrossRefPubMed

38.

Skalova A, Vanecek T, Simpson RH, Vazmitsel MA, Majewska H, Mukensnabl P, Hauer L, Andrle P, Hosticka L, Grossmann P, Michal M (2013) CRTC1-MAML2 and CRTC3-MAML2 fusions were not detected in metaplastic Warthin tumor and metaplastic pleomorphic adenoma of salivary glands. Am J Surg Pathol 37(11):1743–1750. https://doi.org/10.1097/PAS.0000000000000065CrossRefPubMed

39.

Tirado Y, Williams MD, Hanna EY, Kaye FJ, Batsakis JG, El-Naggar AK (2007) CRTC1/MAML2 fusion transcript in high grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin’s tumors: implications for histogenesis and biologic behavior. Genes Chromosomes Cancer 46(7):708–715. https://doi.org/10.1002/gcc.20458CrossRefPubMed

40.

Winnes M, Enlund F, Mark J, Stenman G (2006) The MECT1-MAML2 gene fusion and benign Warthin’s tumor: is the MECT1-MAML2 gene fusion specific to mucuepidermoid carcinoma? J Mol Diagn 8(3):394–395. author reply 395–396. https://doi.org/10.2353/jmoldx.2006.060020

41.

Boecker J, Feyerabend B, Tiemann K, Buchwalow I, Wagner KC, Oldhafer KJ, Andruszkow J, Daniels T, Boessow T, Boecker W, Neumann UP (2020) Adenosquamous carcinoma of the pancreas comprise a heterogeneous group of tumors with the worst outcome: a clinicopathological analysis of 25 cases identified in 562 pancreatic carcinomas resected with curative intent. Pancreas 49(5):683–691. https://doi.org/10.1097/MPA.0000000000001548CrossRefPubMed

42.

Saeki K, Ohishi Y, Matsuda R, Mochidome N, Miyasaka Y, Yamamoto H, Koga Y, Maehara Y, Nakamura M, Oda Y (2018) “Pancreatic mucoepidermoid carcinoma” is not a pancreatic counterpart of CRTC1/3-MAML2 fusion gene-related mucoepidermoid carcinoma of the salivary gland, and may more appropriately be termed pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features. Am J Surg Pathol 42(11):1419–1428. https://doi.org/10.1097/PAS.0000000000001135CrossRefPubMed

Title: Mucoepidermoid carcinoma of the salivary glands revisited with special reference to histologic grading and CRTC1/3-MAML2 genotyping
Authors: André Fehr
Sarah Werenicz
Pietro Trocchi
Markus Falk
Reinhard E. Friedrich
Angelika Stammler
Andreas Stang
Florian Oesterling
Laura Khil
Göran Stenman
Werner Böcker
Katharina Tiemann
Thomas Löning
Publication date: 01-11-2021
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 5/2021
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-021-03146-x

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Mucoepidermoid carcinoma of the salivary glands revisited with special reference to histologic grading and CRTC1/3-MAML2 genotyping

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2021

Diagnostic and prognostic value of tumor-infiltrating B cells in lymph node metastases of papillary thyroid carcinoma

Malignant phyllodes tumour of the breast mimicking endometriosis

Multifocal in situ mantle cell neoplasia of the ileocecal region: a case report with simultaneous nodal and extranodal involvement

Immunopathological analysis of the expression of glomerular exostosin 1 and exostosin 2 in Japanese patients with lupus nephritis

Morphologically malignant nodular fasciitis with CALD1-USP6 fusion

Application of biomarkers in the diagnosis of uncertain samples of core needle biopsy of thyroid nodules