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Atypical cartilage in type II germ cell tumors of the mediastinum show significantly different patterns of IDH1/2 mutations from conventional chondrosarcoma

Abstract

Neoplastic cartilage is a common component of teratomas in type II germ cell tumors. Although IDH1/2 mutations have been well-described in somatic cartilaginous tumors, ranging from benign enchondromas to highly aggressive dedifferentiated chondrosarcomas, the presence of IDH1/2 mutations in cartilaginous neoplasms arising from germ cell tumors has not been previously investigated. To better understand the relationship between these tumors and their bone/soft tissue counterpart, we studied the IDH1/2 mutational status of 20 cases of primary mediastinal mixed germ cell tumors with areas of readily identifiable cartilaginous differentiation. Our study found that cartilaginous lesions arising in germ cell tumors have a different frequency and distribution of IDH1/2 mutations compared to those at somatic sites. We identified IDH1/2 mutations in only 15% (3/20) of cases, compared to a frequency in the literature among differentiated chondroid tumors of bone and soft tissue of 54%, a highly significant decreased frequency (p = 0.0011; chi-square test). Furthermore, they were exclusively IDH2 R172 mutations that occurred at a non-significant, increased frequency in the germ cell tumor group compared to conventional chondrosarcoma (15% vs. 5%, respectively, p > 0.05, chi-square test). The unexpected finding, therefore, was entirely attributable to the absence of IDH1 R132 mutation in chondroid neoplasia of germ cell origin (p < 0.00001, Fisher exact test). Our results suggest that a subset of cartilaginous lesions arising within type II germ cell tumors have a similar oncogenic mechanism to their bone/soft tissue counterpart but that the majority form using different oncogenic mechanisms compared to their somatic counterparts.

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Fig. 1: Varied morphologic appearance of hyaline cartilage in teratoma component.
Fig. 2: Additional morphologic findings.
Fig. 3: Immunohistochemical findings with anti-IDH1/2 mutant antibody.

Data availability

All data generated or analyzed during this study are included in this published article.

References

  1. Oosterhuis JW, Looijenga LH. Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer 5, 210–222 (2005)

  2. Oosterhuis JW, Looijenga LH. Human germ cell tumours from a developmental perspective. Nat Rev Cancer 19, 522–537 (2019)

  3. Mostert MC, Verkerk AJ, van de Pol M, J Heighway, P Marynen, C Rosenberg et al. Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults. Oncogene 16, 2617–2627 (1998)

  4. Colecchia M, Necchi A, Paolina B, Nicolai N, Salvioni R. Teratoma with somatic-type malignant components in germ cell tumors of the testis: a clinicopathologic analysis of 40 cases with outcome correlation. Int J Surg Pathol 19, 321–327 (2011)

  5. Magers MJ, Kao CD, Cole CD, Rice KR, Foster RS, Einhorn LH. “Somatic-type” malignancies arising from testicular germ cell tumors: a clinicopathologic study of 124 cases with emphasis on glandular tumors supporting frequent yolk sac tumor origin. Am J Surg Pathol 38, 1396–1409 (2014)

  6. Guo CC., Punar M, Contreras AL, Tu SM, Pisters L, Tamboli, P. Testicular germ cell tumors with sarcomatous components: an analysis of 33 cases. Am J Surg Pathol 33 (8), 1173–1178 (2009).

  7. Motzer RJ, Amsterdam A, Prieto V, Sheinfeld J, Murty VV, Mazumdar M. Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors. J Urol 159, 133–138 (1998)

  8. Matoso A, Idrees MT, Rodriguez FJ, Ibrahim J, Perrino CM, Ulbright TM, et al. Neuroglial differentiation and neoplasms in testicular germ cell tumors lack immunohistochemical evidence of alterations characteristic of their CNS counterparts: a study of 13 cases. Am J Surg Pathol 43, 422–431 (2019)

  9. Levy DR, Agaram NP, Kao CS, Franks SE, Kesler KA, Stram AR, et al. Vasculogenic mesenchymal tumor: a clinicopathologic and molecular study of 55 cases of a distinctive neoplasm originating from mediastinal yolk sac tumor and an occasional precursor to angiosarcoma. Am J Surg Pathol 45, 463–476 (2021)

  10. Chen S, Fritchie K, Wei S, Ali N, Curless K, Shen T et al. Diagnostic utility of IDH1/2 mutations to distinguish dedifferentiated chondrosarcoma from undifferentiated pleomorphic sarcoma of bone. Hum Pathol 65, 239–246 (2017)

  11. Gondim DD, Gener MA, Curless KL, Cohen-Gadol AA, Hattab EM, Cheng L. Determining IDH-Mutational Status in Gliomas Using IDH1-R132H Antibody and Polymerase Chain Reaction. Appl Immunohistochem Mol Morphol 27, 722–725 (2019)

  12. Moran CA, Suster S. Primary germ cell tumors of the mediastinum: I. Analysis of 322 cases with special emphasis on teratomatous lesions and a proposal for histopathologic classification and clinical staging. Cancer 80, 681–690 (1997)

  13. Nichols CR, Hoffman R, Einhorn LH, Williams SD, Wheeler LA, Garnick MB. Hematologic malignancies associated with primary mediastinal germ-cell tumors. Ann Intern Med 102, 603–609 (1985)

  14. Ladanyi M, Samaniego F, Reuter VE, Motzer RJ, Jhanwar SC, Bosl GJ et al. Cytogenetic and immunohistochemical evidence for germ cell origin of a subset of acute leukemias associated with mediastinal germ cell tumors. J Natl Cancer Inst 82, 221–227 (1990)

  15. Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer 40, 818–831 (1977)

  16. Losman JA, Kaelin WG Jr What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 27, 836–52 (2013)

  17. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009)

  18. Yen KE, Schenkein DP. Cancer-associated isocitrate dehydrogenase mutations. Oncologist 17, 5–8 (2012)

  19. Schaefer IM, Hornick JL, Bovee JVMG. The role of metabolic enzymes in mesenchymal tumors and tumor syndromes: genetics, pathology and molecular mechanisms. Laboratory Investigation 98, 414–426 (2018)

  20. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 360, 765–773 (2009)

  21. Abbas S, Lugthart S, Kavelaars FG, Schelen A, Koenders JE, Zeilemaker A et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia (AML): prevalence and prognostic value. Blood 116, 2122–2126 (2010)

  22. Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Kronke J, Bullinger L, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 28, 3636–3643 (2010)

  23. Jo VY, Chau NG, Hornick JL, Krane JF, Sholl LM. Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma. Mod Pathol 30, 650–659 (2017)

  24. Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene 29, 6409–6417 (2010)

  25. Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 17, 72–79 (2012)

  26. Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Seo SI, et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer 125, 353–355 (2009)

  27. Gaal J, Burnichon N, Korpershoek E, Roncelin I, Bertherat J, Plouin PF, et al. Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas. J Clin Endocrinol Metab 95, 1274–1278 (2010)

  28. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224, 334–343 (2011)

  29. Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, Aldape KP, Yung WK, Salama SR, Cooper LA, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372, 2481–2498 (2015)

  30. Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A. Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol 118, 599–601 (2009)

  31. Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and olidgogendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 118, 469–474 (2009)

  32. Thol F, Damm F, Wagner K, Gohring G, Schlegelberger B, Hoelzer D, et al. Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood 116, 614–616 (2010)

  33. Kerr DA, Lopez HU, Deshpande V, Hornicek FJ, Duan Z, Zhang Y, et al. Molecular distinction of chondrosarcoma from chondroblastic osteosarcoma through IDH1/2 mutations. Am J Surg Pathol 37, 787–795 (2013)

  34. Vuong HG, Ngo TNM, Dunn IF. Prognostic importance of IDH mutations in chondrosarcoma: An individual patient data meta-analysis. Cancer Medicine 10, 4415–4423 (2021)

  35. Pansuriya TC, van Eijk R, d’Adamo P, van Ruler MAJH, Kuijjer ML, Oosting J, et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 43, 1256–1261 (2011)

  36. Szuhai K, Jennes I, de Jong D, Bovee JVMG, Wiweger M, Wuyts W, et al. Tiling resolution array-CGH shows that somatic mosaic deletion of the EXT gene is causative in EXT gene mutation-negative multiple osteochondroma patients. Hum Mutat 32, E2036–2049 (2011)

  37. Tallegas M, Miquelestorena-Standley E, Labit-Bouvier C, Badoual C, Francois A, Gomez-Brouchet A, et al. IDH mutation status in a series of 88 head and neck chondrosarcomas: different profile between tumors of the skull base and tumors involving the facial skeleton and the laryngotracheal tract. Hum Pathol 84, 183–191 (2019)

  38. Dorssers LCJ, Gillis AJM, Stoop H, van Marion R, Nieboer MM, van Riet J, et al. Molecular heterogeneity and early metastatic clone selection in testicular germ cell cancer development. Br J Cancer 120, 444–452 (2019)

  39. Cleven AHG, Suijker J, Agrogiannis G, Briaire-de Bruijn IH, Frizzell N, Hoekstra AS, et al. IDH1 or -2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas. Clin Sarcoma Res 7, 8 (2017)

  40. Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75, 1560–1566 (2010)

  41. Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27, 4150–4154 (2009)

  42. Lugowska I, Teterycz P, Mikula M, Kulecka M, Kluska A, Balabas A, et al. IDH1/2 mutations predict shorter survival in chondrosarcoma. J Cancer 9, 998–1005 (2018)

  43. Zhu GG, Nafa K, Agaram N, Zehir A, Benayed R, Sadowska J, et al. Genomic profiling identifies association of IDH1/IDH2 mutation with longer relapse-free and metastasis-free survival in high-grade chondrosarcoma. Clin Cancer Res 26, 419–427 (2020)

  44. Kanamori H, Kitamura Y, Kimura T, Yoshida K, Sasaki H. Genetic characterization of skull base chondrosarcomas. J Neurosurg 123, 1036–1041 (2015)

  45. Li L, Paz AC, Wilky BA, Johnson B, Galoian K, Rosenberg EA, et al. Treatment with a small molecule mutant IDH1 inhibitor suppresses tumorigenic activity and decreases production of the oncometabolite 2-hydroxyglutarate in human chondrosarcoma cells. PLoS ONE 10, e0133813 (2015)

  46. Suijker J, Oosting J, Koornneef A, Struys EA, Salomons GS, Schaap FG, et al. Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines. Oncotarget 6, 12505–12519 (2015)

  47. Kim ES. Enasidenib: first global approval. Drugs 77, 1705–1711 (2017)

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LMW performed study concept and design, performed development of methodology and writing, and reviewed and revised the paper. MS and JDS provided acquisition, analysis and interpretation of data. LC provided acquisition, analysis and interpretation of data and reviewed and revised the paper. TMU performed study concept and design, reviewed and revised the paper and performed statistical analysis. All authors read and approved the final paper.

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Correspondence to Laura M. Warmke.

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The study was performed in accordance with the Declaration of Helsinki. No identifying data is included in the study.

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Warmke, L.M., Cheng, L., Sperling, R.M. et al. Atypical cartilage in type II germ cell tumors of the mediastinum show significantly different patterns of IDH1/2 mutations from conventional chondrosarcoma. Mod Pathol (2022). https://doi.org/10.1038/s41379-022-01106-7

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