Leiomyoma with Bizarre Nuclei: a Study of 108 Cases Focusing on Clinicopathological Features, Morphology, and Fumarate Hydratase Alterations

Abstract

Leiomyoma with bizarre nuclei (LBN) is an uncommon variant of uterine smooth muscle neoplasm. Involvement of fumarate hydratase (FH) has been suggested in the pathogenesis of a subset of LBN. The goal of our study is to assess the clinicopathological, morphological, immunohistochemical and molecular findings focusing on FH in LBNs (n = 108) and compare it with the findings in usual leiomyomas (UL; n = 50) and leiomyosarcomas (LMS; n = 42). Immunohistochemically, loss of FH expression was found in 67/108 of LBN, 1/50 of UL and in no LMS. Class 4/5 FH mutations were detected in 15/53 LBN with sufficient DNA quality for molecular analysis. Pathogenic variants of the FH gene were detected in neither UL nor LMS. Local recurrence after surgery was present in 18/92 of LBN patients, 7 of which were histologically verified and 2 of which were found to be LBN. Our results confirmed that LBN behave in a benign fashion, although they may relapse. FH gene mutations were a common finding only in LBN, but not in UL and LMS. Immunohistochemistry with an antibody against FH seems to have a good sensitivity (87%) and moderate specificity (58%) with regard to predicting FH gene mutations and could be used as a screening method in tumors with features suggestive of FH alterations to identify patients who are at risk for the FH aberrations.

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References

  1. 1.

    Bell SW, Kempson RL, Hendrickson MR (1994) Problematic uterine smooth muscle neoplasms. A clinicopathologic study of 213 cases. Am J Surg Pathol 18(6):535–558

    CAS  Article  Google Scholar 

  2. 2.

    Kurman RJ, Carcangiu ML, Young RH, Herrington CSE (2014) WHO Classification of tumours of female reproductive organs, 4th edn. IARC, Lyon:307

    Google Scholar 

  3. 3.

    Liegl-Atzwanger B, Heitzer E, Flicker K, Muller S, Ulz P, Saglam O, Tavassoli F, Devouassoux-Shisheboran M, Geigl J, Moinfar F (2016) Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors. Mod Pathol 29(10):1262–1277. https://doi.org/10.1038/modpathol.2016.107

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Makinen N, Kampjarvi K, Frizzell N, Butzow R, Vahteristo P (2017) Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors. Mol Cancer 16(1):101. https://doi.org/10.1186/s12943-017-0672-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Ubago JM, Zhang Q, Kim JJ, Kong B, Wei JJ (2016) Two subtypes of atypical Leiomyoma: clinical, histologic, and molecular analysis. Am J Surg Pathol 40(7):923–933. https://doi.org/10.1097/PAS.0000000000000646

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Nibert M, Heim S (1990) Uterine leiomyoma cytogenetics. Genes Chromosomes Cancer 2(1):3–13

    CAS  Article  Google Scholar 

  7. 7.

    Lehtonen R, Kiuru M, Vanharanta S, Sjoberg J, Aaltonen LM, Aittomaki K, Arola J, Butzow R, Eng C, Husgafvel-Pursiainen K, Isola J, Jarvinen H, Koivisto P, Mecklin JP, Peltomaki P, Salovaara R, Wasenius VM, Karhu A, Launonen V, Nupponen NN, Aaltonen LA (2004) Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. Am J Pathol 164(1):17–22. https://doi.org/10.1016/S0002-9440(10)63091-X

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Harrison WJ, Andrici J, Maclean F, Madadi-Ghahan R, Farzin M, Sioson L, Toon CW, Clarkson A, Watson N, Pickett J, Field M, Crook A, Tucker K, Goodwin A, Anderson L, Srinivasan B, Grossmann P, Martinek P, Ondic O, Hes O, Trpkov K, Clifton-Bligh RJ, Dwight T, Gill AJ (2016) Fumarate hydratase-deficient uterine leiomyomas occur in both the syndromic and sporadic settings. Am J Surg Pathol 40(5):599–607. https://doi.org/10.1097/PAS.0000000000000573

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Ylisaukko-oja SK, Kiuru M, Lehtonen HJ, Lehtonen R, Pukkala E, Arola J, Launonen V, Aaltonen LA (2006) Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. Int J Cancer 119(2):283–287. https://doi.org/10.1002/ijc.21798

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Barker KT, Spendlove HE, Banu NS, Bridge JA, Fisher C, Shipley J, Garrett M, Manyonda I, Houlston RS (2006) No evidence for epigenetic inactivation of fumarate hydratase in leiomyomas and leiomyosarcomas. Cancer Lett 235(1):136–140. https://doi.org/10.1016/j.canlet.2005.04.017

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Alam NA, Olpin S, Rowan A, Kelsell D, Leigh IM, Tomlinson IP, Weaver T (2005) Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer. J Mol Diagn 7(4):437–443. https://doi.org/10.1016/S1525-1578(10)60574-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Llamas-Velasco M, Requena L, Adam J, Frizzell N, Hartmann A, Mentzel T (2016) Loss of fumarate hydratase and aberrant protein succination detected with S-(2-Succino)-cysteine staining to identify patients with Multiple cutaneous and uterine Leiomyomatosis and hereditary Leiomyomatosis and renal cell cancer syndrome. Am J Dermatopathol 38(12):887–891. https://doi.org/10.1097/DAD.0000000000000580

    Article  PubMed  Google Scholar 

  13. 13.

    Wei JJ (2016) Atypical leiomyoma with features suggesting of fumarate hydratase mutation. Int J Gynecol Pathol 35(6):531–536. https://doi.org/10.1097/PGP.0000000000000276

    Article  PubMed  Google Scholar 

  14. 14.

    Linehan WM, Rouault TA (2013) Molecular pathways: fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer. Clin Cancer Res 19(13):3345–3352. https://doi.org/10.1158/1078-0432.CCR-13-0304

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Tong WH, Sourbier C, Kovtunovych G, Jeong SY, Vira M, Ghosh M, Romero VV, Sougrat R, Vaulont S, Viollet B, Kim YS, Lee S, Trepel J, Srinivasan R, Bratslavsky G, Yang Y, Linehan WM, Rouault TA (2011) The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels. Cancer Cell 20(3):315–327. https://doi.org/10.1016/j.ccr.2011.07.018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA, Multiple Leiomyoma C (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30(4):406–410. https://doi.org/10.1038/ng849

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Trpkov K, Hes O, Agaimy A, Bonert M, Martinek P, Magi-Galluzzi C, Kristiansen G, Luders C, Nesi G, Comperat E, Sibony M, Berney DM, Mehra R, Brimo F, Hartmann A, Husain A, Frizzell N, Hills K, Maclean F, Srinivasan B, Gill AJ (2016) Fumarate hydratase-deficient renal cell carcinoma is strongly correlated with fumarate hydratase mutation and hereditary leiomyomatosis and renal cell carcinoma syndrome. Am J Surg Pathol 40(7):865–875. https://doi.org/10.1097/PAS.0000000000000617

    Article  PubMed  Google Scholar 

  18. 18.

    Buelow B, Cohen J, Nagymanyoki Z, Frizzell N, Joseph NM, McCalmont T, Garg K (2016) Immunohistochemistry for 2-Succinocysteine (2SC) and Fumarate Hydratase (FH) in cutaneous leiomyomas may aid in identification of patients with HLRCC (Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome). Am J Surg Pathol 40(7):982–988. https://doi.org/10.1097/PAS.0000000000000626

    Article  PubMed  Google Scholar 

  19. 19.

    Wei MH, Toure O, Glenn GM, Pithukpakorn M, Neckers L, Stolle C, Choyke P, Grubb R, Middelton L, Turner ML, Walther MM, Merino MJ, Zbar B, Linehan WM, Toro JR (2006) Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 43(1):18–27. https://doi.org/10.1136/jmg.2005.033506

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F (2016) The Ensembl variant effect predictor. Genome Biol 17(1):122. https://doi.org/10.1186/s13059-016-0974-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Bennett JA, Weigelt B, Chiang S, Selenica P, Chen YB, Bialik A, Bi R, Schultheis AM, Lim RS, Ng CKY, Morales-Oyarvide V, Young RH, Reuter VE, Soslow RA, Oliva E (2017) Leiomyoma with bizarre nuclei: a morphological, immunohistochemical and molecular analysis of 31 cases. Mod Pathol 30(10):1476–1488. https://doi.org/10.1038/modpathol.2017.56

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Croce S, Young RH, Oliva E (2014) Uterine leiomyomas with bizarre nuclei: a clinicopathologic study of 59 cases. Am J Surg Pathol 38(10):1330–1339. https://doi.org/10.1097/PAS.0000000000000249

    Article  PubMed  Google Scholar 

  23. 23.

    Dastranj Tabrizi A, Ghojazadeh M, Thagizadeh Anvar H, Vahedi A, Naji S, Mostafidi E, Berenjian S (2015) Immunohistochemical profile of uterine leiomyoma with bizarre nuclei; comparison with conventional leiomyoma, smooth muscle tumors of uncertain malignant potential and leiomyosarcoma. Adv Pharm Bull 5(Suppl 1):683–687. https://doi.org/10.15171/apb.2015.093

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Kefeli M, Caliskan S, Kurtoglu E, Yildiz L, Kokcu A (2017) Leiomyoma with bizarre nuclei: clinical and pathologic features of 30 patients. Int J Gynecol Pathol 37:379–387. https://doi.org/10.1097/PGP.0000000000000425

    Article  Google Scholar 

  25. 25.

    Liang Y, Zhang X, Chen X, Lu W (2015) Diagnostic value of progesterone receptor, p16, p53 and pHH3 expression in uterine atypical leiomyoma. Int J Clin Exp Pathol 8(6):7196–7202

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Ly A, Mills AM, McKenney JK, Balzer BL, Kempson RL, Hendrickson MR, Longacre TA (2013) Atypical leiomyomas of the uterus: a clinicopathologic study of 51 cases. Am J Surg Pathol 37(5):643–649. https://doi.org/10.1097/PAS.0b013e3182893f36

    Article  PubMed  Google Scholar 

  27. 27.

    Sung CO, Ahn G, Song SY, Choi YL, Bae DS (2009) Atypical leiomyomas of the uterus with long-term follow-up after myomectomy with immunohistochemical analysis for p16INK4A, p53, Ki-67, estrogen receptors, and progesterone receptors. Int J Gynecol Pathol 28(6):529–534. https://doi.org/10.1097/PGP.0b013e3181a2b8d3

    Article  PubMed  Google Scholar 

  28. 28.

    Zhang Q, Poropatich K, Ubago J, Xie J, Xu X, Frizzell N, Kim J, Kong B, Wei JJ (2017) Fumarate hydratase mutations and alterations in Leiomyoma with bizarre nuclei. Int J Gynecol Pathol 37:421–430. https://doi.org/10.1097/PGP.0000000000000447

    CAS  Article  Google Scholar 

  29. 29.

    Kalogiannidis I, Stavrakis T, Dagklis T, Petousis S, Nikolaidou C, Venizelos I, Rousso D (2016) A clinicopathological study of atypical leiomyomas: benign variant leiomyoma or smooth-muscle tumor of uncertain malignant potential. Oncol Lett 11(2):1425–1428. https://doi.org/10.3892/ol.2015.4062

    Article  PubMed  Google Scholar 

  30. 30.

    Mills AM, Ly A, Balzer BL, Hendrickson MR, Kempson RL, McKenney JK, Longacre TA (2013) Cell cycle regulatory markers in uterine atypical leiomyoma and leiomyosarcoma: immunohistochemical study of 68 cases with clinical follow-up. Am J Surg Pathol 37(5):634–642. https://doi.org/10.1097/PAS.0b013e318287779c

    Article  PubMed  Google Scholar 

  31. 31.

    Pang SJ, Li CC, Shen Y, Liu YZ, Shi YQ, Liu YX (2015) Value of counting positive PHH3 cells in the diagnosis of uterine smooth muscle tumors. Int J Clin Exp Pathol 8(5):4418–4426

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Dundr P, Povysil C, Tvrdik D, Mara M (2007) Uterine leiomyomas with inclusion bodies: an immunohistochemical and ultrastructural analysis of 12 cases. Pathol Res Pract 203(3):145–151. https://doi.org/10.1016/j.prp.2006.12.008

    Article  PubMed  Google Scholar 

  33. 33.

    Makinen N, Vahteristo P, Kampjarvi K, Arola J, Butzow R, Aaltonen LA (2013) MED12 exon 2 mutations in histopathological uterine leiomyoma variants. Eur J Hum Genet 21(11):1300–1303. https://doi.org/10.1038/ejhg.2013.33

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Makinen N, Aavikko M, Heikkinen T, Taipale M, Taipale J, Koivisto-Korander R, Butzow R, Vahteristo P (2016) Exome sequencing of uterine leiomyosarcomas identifies frequent mutations in TP53, ATRX, and MED12. PLoS Genet 12(2):e1005850. https://doi.org/10.1371/journal.pgen.1005850

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Reyes C, Karamurzin Y, Frizzell N, Garg K, Nonaka D, Chen YB, Soslow RA (2014) Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry. Mod Pathol 27(7):1020–1027. https://doi.org/10.1038/modpathol.2013.215

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Sanz-Ortega J, Vocke C, Stratton P, Linehan WM, Merino MJ (2013) Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol 37(1):74–80. https://doi.org/10.1097/PAS.0b013e31825ec16f

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Joseph NM, Solomon DA, Frizzell N, Rabban JT, Zaloudek C, Garg K (2015) Morphology and immunohistochemistry for 2SC and FH aid in detection of fumarate hydratase gene aberrations in uterine leiomyomas from young patients. Am J Surg Pathol 39(11):1529–1539. https://doi.org/10.1097/PAS.0000000000000520

    Article  PubMed  Google Scholar 

  38. 38.

    Miettinen M, Felisiak-Golabek A, Wasag B, Chmara M, Wang Z, Butzow R, Lasota J (2016) Fumarase-deficient uterine leiomyomas: an immunohistochemical, molecular genetic, and clinicopathologic study of 86 cases. Am J Surg Pathol 40(12):1661–1669. https://doi.org/10.1097/PAS.0000000000000703

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Picaud S, Kavanagh KL, Yue WW, Lee WH, Muller-Knapp S, Gileadi O, Sacchettini J, Oppermann U (2011) Structural basis of fumarate hydratase deficiency. J Inherit Metab Dis 34(3):671–676. https://doi.org/10.1007/s10545-011-9294-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Chuang GS, Martinez-Mir A, Geyer A, Engler DE, Glaser B, Cserhalmi-Friedman PB, Gordon D, Horev L, Lukash B, Herman E, Cid MP, Brenner S, Landau M, Sprecher E, Garcia Muret MP, Christiano AM, Zlotogorski A (2005) Germline fumarate hydratase mutations and evidence for a founder mutation underlying multiple cutaneous and uterine leiomyomata. J Am Acad Dermatol 52(3 Pt 1):410–416. https://doi.org/10.1016/j.jaad.2004.08.051

    Article  PubMed  Google Scholar 

  41. 41.

    Siegler L, Erber R, Burghaus S, Brodkorb T, Wachter D, Wilkinson N, Bolton J, Stringfellow H, Haller F, Beckmann MW, Hartmann A, Agaimy A (2018) Fumarate hydratase (FH) deficiency in uterine leiomyomas: recognition by histological features versus blind immunoscreening. Virchows Arch 472(5):789–796. https://doi.org/10.1007/s00428-018-2292-6

    CAS  Article  PubMed  Google Scholar 

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Funding

This work was supported by Ministry of Health, Czech Republic (Conceptual development of research organization 64165, General University Hospital in Prague), by Charles University (Project Progres Q28/LF1, UNCE 204065 and SVV 260367), by European Regional Development Fund, project EF16_013/0001674 and BBMRI_CZ LM2015089, and by OPPK (Research Laboratory of Tumor Diseases, CZ.2.16/3.1.00/24509).

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Correspondence to Ivana Tichá or Pavel Dundr.

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In compliance with the Helsinki Declaration, the project has been approved by Ethics Committee of the General University Hospital, Prague (reference number č.j. 98/16 Grant RVO-VFN 64165).

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Gregová, M., Hojný, J., Němejcová, K. et al. Leiomyoma with Bizarre Nuclei: a Study of 108 Cases Focusing on Clinicopathological Features, Morphology, and Fumarate Hydratase Alterations. Pathol. Oncol. Res. 26, 1527–1537 (2020). https://doi.org/10.1007/s12253-019-00739-5

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Keywords

  • Leiomyoma with bizarre nuclei
  • Usual leiomyoma
  • Leiomyosarcoma
  • Fumarate hydratase