The value of immunohistochemical methods in diagnosing mesenchymal tumours of the uterus

Česká verzia

Authors: Pavel Dundr; Mária Gregová; Kristýna Němejcová ; Michaela Bártů; Rosalie Jana Bennett; Ivana Stružinská
Authors place of work: Ústav patologie 1. LF UK a VFN v Praze
Published in the journal: Čes.-slov. Patol., 57, 2021, No. 2, p. 86-95
Category: Reviews Article

Summary

The goal of this manuscript is to provide a comprehensive overview of the use of immunohistochemical methods in diagnosing mesenchymal tumours of the uterus. The main points discussed include, especially, the issue of determining smooth muscle differentiation, the differential diagnosis between smooth muscle and endometrial stromal tumours, and the diagnosis of inflammatory myofibroblastic tumour. The role of immunohistochemical examination in the diagnosis of some of the only recently definedentities such as YWHAE-altered high grade endometrial stromal sarcoma (HG-ESS), BCOR-altered HG-ESS, tumours with NTRK fusion, and SMARCA4-deficient sarcomas is also discussed. The last aspect of this work is an analysis of the significance of immunohistochemical methods in the determination of the biological behaviour of leiomyocellular tumours. The issue of their molecular classification for those lesions associated with the presence of recurrent molecular aberrations is also discussed.

Keywords:

mesenchymal uterine tumors – smooth muscle tumors – endometrial stromal tumors – undifferentiated uterine sarcoma – immunohistochemistry – molecular classification

Zdroje

1. Prat J, Mbatani. Uterine sarcomas. Int J Gynaecol Obstet 2015; 131 Suppl 2: S105-110.

2. Dundr P, Fischerová D, Povýšil C, et al. Uterine tumors with neuroectodermal differentiation. A report of 4 cases. Pathol Oncol Res 2010; 16(4): 601-608.

3. Dundr P, Fischerová D, Povýšil C, Tvrdik D, Cibula D. Primary synovial sarcoma of the uterus. Pathol Oncol Res 2012; 18(2): 529-533.

4. Cotzia P, Benayed R, Mullaney K, et al. Undifferentiated uterine sarcomas represent under-recognized high-grade endometrial stromal sarcomas. Am J Surg Pathol 2019; 43(5): 662-669.

5. Micci F, Brunetti M, Dal Cin P, et al. Fusion of the genes brd8 and phf1 in endometrial stromal sarcoma. Genes Chromosomes Cancer 2017; 56(12): 841-845.

6. Busca A, Gulavita P, Parra-Herran C, Islam S. Ifitm1 outperforms cd10 in differentiating low-grade endometrial stromal sarcomas from smooth muscle neoplasms of the uterus. Int J Gynecol Pathol 2017;

7. Parra-Herran CE, Yuan L, Nucci MR, Quade BJ. Targeted development of specific biomarkers of endometrial stromal cell differentiation using bioinformatics: The ifitm1 model. Mod Pathol 2014; 27(4): 569-579.

8. Chu PG, Arber DA, Weiss LM, Chang KL. Utility of cd10 in distinguishing between endometrial stromal sarcoma and uterine smooth muscle tumors: An immunohistochemical comparison of 34 cases. Mod Pathol 2001; 14(5): 465-471.

9. Mccluggage WG, Sumathi VP, Maxwell P. Cd10 is a sensitive and diagnostically useful immunohistochemical marker of normal endometrial stroma and of endometrial stromal neoplasms. Histopathology 2001; 39(3): 273-278.

10. Abeler VM, Nenodovic M. Diagnostic immunohistochemistry in uterine sarcomas: A study of 397 cases. Int J Gynecol Pathol 2011; 30(3): 236-243.

11. Carvalho JC, Thomas DG, Lucas DR. Cluster analysis of immunohistochemical markers in leiomyosarcoma delineates specific anatomic and gender subgroups. Cancer 2009; 115(18): 4186-4195.

12. Bodner K, Bodner-Adler B, Kimberger O, et al. Estrogen and progesterone receptor expression in patients with uterine leiomyosarcoma and correlation with different clinicopathological parameters. Anticancer Res 2003; 23(1B): 729-732.

13. Akhan SE, Yavuz E, Tecer A, et al. The expression of ki-67, p53, estrogen and progesterone receptors affecting survival in uterine leiomyosarcomas. A clinicopathologic study. Gynecol Oncol 2005; 99(1): 36-42.

14. Hwang H, Matsuo K, Duncan K, et al. Immunohistochemical panel to differentiate endometrial stromal sarcoma, uterine leiomyosarcoma and leiomyoma: Something old and something new. J Clin Pathol 2015; 68(9): 710-717.

15. Chiang S, Lee CH, Stewart CJR, et al. Bcor is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology. Mod Pathol 2017; 30(9): 1251-1261.

16. Klein WM, Kurman RJ. Lack of expression of c-kit protein (cd117) in mesenchymal tumors of the uterus and ovary. Int J Gynecol Pathol 2003; 22(2): 181-184.

17. Simpson KW, Albores-Saavedra J. Hmb-45 reactivity in conventional uterine leiomyosarcomas. Am J Surg Pathol 2007; 31(1): 95-98.

18. Rush DS, Tan J, Baergen RN, Soslow RA. H-caldesmon, a novel smooth muscle-specific antibody, distinguishes between cellular leiomyoma and endometrial stromal sarcoma. Am J Surg Pathol 2001; 25(2): 253-258.

19. Toki T, Shimizu M, Takagi Y, Ashida T, Konishi I. Cd10 is a marker for normal and neoplastic endometrial stromal cells. Int J Gynecol Pathol 2002; 21(1): 41-47.

20. Wang L, Felix JC, Lee JL, et al. The proto-oncogene c-kit is expressed in leiomyosarcomas of the uterus. Gynecol Oncol 2003; 90(2): 402-406.

21. Koivisto-Korander R, Butzow R, Koivisto AM, Leminen A. Immunohistochemical studies on uterine carcinosarcoma, leiomyosarcoma, and endometrial stromal sarcoma: Expression and prognostic importance of ten different markers. Tumour Biol 2011; 32(3): 451-459.

22. Allen MM, Douds JJ, Liang SX, et al. An immunohistochemical analysis of stathmin 1 expression in uterine smooth muscle tumors: Differential expression in leiomyosarcomas and leiomyomas. Int J Clin Exp Pathol 2015; 8(3): 2795-2801.

23. Zhai YL, Kobayashi Y, Mori A, et al. Expression of steroid receptors, ki-67, and p53 in uterine leiomyosarcomas. Int J Gynecol Pathol 1999; 18(1): 20-28.

24. Robin YM, Penel N, Perot G, et al. Transgelin is a novel marker of smooth muscle differentiation that improves diagnostic accuracy of leiomyosarcomas: A comparative immunohistochemical reappraisal of myogenic markers in 900 soft tissue tumors. Mod Pathol 2013; 26(4): 502-510.

25. Tawfik O, Rao D, Nothnick WB, et al. Transgelin, a novel marker of smooth muscle differentiation, effectively distinguishes endometrial stromal tumors from uterine smooth muscle tumors. Int J Gynecol Obstet Reprod Med Res 2014; 1(1): 26-31.

26. Makinen N, Kampjarvi K, Frizzell N, Butzow R, Vahteristo P. Characterization of med12, hmga2, and fh alterations reveals molecular variability in uterine smooth muscle tumors. Mol Cancer 2017; 16(1): 101.

27. Makinen N, Vahteristo P, Kampjarvi K, et al. Med12 exon 2 mutations in histopathological uterine leiomyoma variants. Eur J Hum Genet 2013; 21(11): 1300-1303.

28. Croce S, Chibon F. Med12 and uterine smooth muscle oncogenesis: State of the art and perspectives. Eur J Cancer 2015; 51(12): 1603-1610.

29. Gregova M, Hojny J, Nemejcova K, et al. Leiomyoma with bizarre nuclei: A study of 108 cases focusing on clinicopathological features, morphology, and fumarate hydratase alterations. Pathol Oncol Res 2020; 26(3): 1527-1537.

30. Pang SJ, Li CC, Shen Y, et al. Value of counting positive phh3 cells in the diagnosis of uterine smooth muscle tumors. Int J Clin Exp Pathol 2015; 8(5): 4418-4426.

31. Chow KL, Tse KY, Cheung CL, et al. The mitosis-specific marker phosphohistone-h3 (phh3) is an independent prognosticator in uterine smooth muscle tumours: An outcome-based study. Histopathology 2017; 70(5): 746-755.

32. Liang Y, Zhang X, Chen X, Lu W. Diagnostic value of progesterone receptor, p16, p53 and phh3 expression in uterine atypical leiomyoma. Int J Clin Exp Pathol 2015; 8(6): 7196-7202.

33. Hewedi IH, Radwan NA, Shash LS. Diagnostic value of progesterone receptor and p53 expression in uterine smooth muscle tumors. Diagn Pathol 2012; 7: 1.

34. Ip PP, Cheung AN, Clement PB. Uterine smooth muscle tumors of uncertain malignant potential (stump): A clinicopathologic analysis of 16 cases. Am J Surg Pathol 2009; 33(7): 992-1005.

35. Atkins KA, Arronte N, Darus CJ, Rice LW. The use of p16 in enhancing the histologic classification of uterine smooth muscle tumors. Am J Surg Pathol 2008; 32(1): 98-102.

36. Azimpouran M, Vazifekhah S, Moslemi F, Piri R, Naghavi-Behzad M. Immunohistochemical profile of uterine leiomyomas; a comparison between different subtypes. Niger Med J 2016; 57(1): 54-58.

37. Bennett JA, Weigelt B, Chiang S, et al. Leiomyoma with bizarre nuclei: A morphological, immunohistochemical and molecular analysis of 31 cases. Mod Pathol 2017; 30(10): 1476-1488.

38. Bodner-Adler B, Bodner K, Czerwenka K, et al. Expression of p16 protein in patients with uterine smooth muscle tumors: An immunohistochemical analysis. Gynecol Oncol 2005; 96(1): 62-66.

39. Cao HY, Yang S, Wang S, Deng LY, Lou JY. Is differential expression of p16ink4a based on the classification of uterine smooth muscle tumors associated with a different prognosis? A meta-analysis. Genet Mol Res 2017; 16(1):

40. Dastranj Tabrizi A, Ghojazadeh M, Thagizadeh Anvar H, et al. Immunohistochemical profile of uterine leiomyoma with bizarre nuclei; comparison with conventional leiomyoma, smooth muscle tumors of uncertain malignant potential and leiomyosarcoma. Adv Pharm Bull 2015; 5(Suppl 1): 683-687.

41. Gannon BR, Manduch M, Childs TJ. Differential immunoreactivity of p16 in leiomyosarcomas and leiomyoma variants. Int J Gynecol Pathol 2008; 27(1): 68-73.

42. Hakverdi S, Gungoren A, Yaldiz M, Hakverdi AU, Toprak S. Immunohistochemical analysis of p16 expression in uterine smooth muscle tumors. Eur J Gynaecol Oncol 2011; 32(5): 513-515.

43. Hall KL, Teneriello MG, Taylor RR, et al. Analysis of Ki-ras, p53, and MDM2 genes in uterine leiomyomas and leiomyosarcomas. Gynecol Oncol 1997; 65(2): 330-335.

44. Huo L, Wang D, Wang W, et al. Oncologic and reproductive outcomes of uterine smooth muscle tumor of uncertain malignant potential: A single center retrospective study of 67 cases. Front Oncol 2020; 10: 647.

45. Chen L, Yang B. Immunohistochemical analysis of p16, p53, and ki-67 expression in uterine smooth muscle tumors. Int J Gynecol Pathol 2008; 27(3): 326-332.

46. Keyhanian K, Lage JM, Chernetsova E, et al. Combination of mcm2 with ki67 and p16 immunohistochemistry can distinguish uterine leiomyosarcomas. Int J Gynecol Pathol 2020; 39(4): 354-361.

47. Maltese G, Fontanella C, Lepori S, et al. Atypical uterine smooth muscle tumors: A retrospective evaluation of clinical and pathologic features. Oncology 2018; 94(1): 1-6.

48. Mills AM, Ly A, Balzer BL, et al. Cell cycle regulatory markers in uterine atypical leiomyoma and leiomyosarcoma: Immunohistochemical study of 68 cases with clinical follow-up. Am J Surg Pathol 2013; 37(5): 634-642.

49. Mittal K, Demopoulos RI. Mib-1 (ki-67), p53, estrogen receptor, and progesterone receptor expression in uterine smooth muscle tumors. Hum Pathol 2001; 32(9): 984-987.

50. O’neill CJ, Mcbride HA, Connolly LE, Mccluggage WG. Uterine leiomyosarcomas are characterized by high p16, p53 and mib1 expression in comparison with usual leiomyomas, leiomyoma variants and smooth muscle tumours of uncertain malignant potential. Histopathology 2007; 50(7): 851-858.

51. Stanescu AD, Nistor E, Sajin M, Stepan AE. Immunohistochemical analysis in the diagnosis of uterine myometrial smooth muscle tumors. Rom J Morphol Embryol 2014; 55(3 Suppl): 1129-1136.

52. Sun X, Mittal K. Mib-1 (ki-67), estrogen receptor, progesterone receptor, and p53 expression in atypical cells in uterine symplastic leiomyomas. Int J Gynecol Pathol 2010; 29(1): 51-54.

53. Sung CO, Ahn G, Song SY, Choi YL, Bae DS. 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 2009; 28(6): 529-534.

54. Ubago JM, Zhang Q, Kim JJ, Kong B, Wei JJ. Two subtypes of atypical leiomyoma: Clinical, histologic, and molecular analysis. Am J Surg Pathol 2016; 40(7): 923-933.

55. Unver NU, Acikalin MF, Oner U, et al. Differential expression of p16 and p21 in benign and malignant uterine smooth muscle tumors. Arch Gynecol Obstet 2011; 284(2): 483-490.

56. Zhang Q, Kanis MJ, Ubago J, et al. The selected biomarker analysis in 5 types of uterine smooth muscle tumors. Hum Pathol 2018; 76: 17-27.

57. Zheng YY, Liu XB, Mao YY, Lin MH. Smooth muscle tumor of uncertain malignant potential (stump): A clinicopathologic analysis of 26 cases. Int J Clin Exp Pathol 2020; 13(4): 818-826.

58. Zhu XQ, Shi YF, Cheng XD, Zhao CL, Wu YZ. Immunohistochemical markers in differential diagnosis of endometrial stromal sarcoma and cellular leiomyoma. Gynecol Oncol 2004; 92(1): 71-79.

59. Ip PP, Lim D, Cheung ANY, Oliva E. Immunoexpression of p16 in uterine leiomyomas with infarct-type necrosis: An analysis of 35 cases. Histopathology 2017; 71(5): 743-750.

60. Slatter TL, Hsia H, Samaranayaka A, et al. Loss of atrx and daxx expression identifies poor prognosis for smooth muscle tumours of uncertain malignant potential and early stage uterine leiomyosarcoma. J Pathol Clin Res 2015; 1(2): 95-105.

61. Oliva E, Young RH, Clement PB, Bhan AK, Scully RE. Cellular benign mesenchymal tumors of the uterus. A comparative morphologic and immunohistochemical analysis of 33 highly cellular leiomyomas and six endometrial stromal nodules, two frequently confused tumors. Am J Surg Pathol 1995; 19(7): 757-768.

62. Oliva E. Cellular mesenchymal tumors of the uterus: A review emphasizing recent observations. Int J Gynecol Pathol 2014; 33(4): 374-384.

63. Agoff SN, Grieco VS, Garcia R, Gown AM. Immunohistochemical distinction of endometrial stromal sarcoma and cellular leiomyoma. Appl Immunohistochem Mol Morphol 2001; 9(2): 164-169.

64. Oliva E, Young RH, Amin MB, Clement PB. An immunohistochemical analysis of endometrial stromal and smooth muscle tumors of the uterus: A study of 54 cases emphasizing the importance of using a panel because of overlap in immunoreactivity for individual antibodies. Am J Surg Pathol 2002; 26(4): 403-412.

65. Rahimi S, Akaev I, Marani C, Chopra M, Yeoh CC. Immunohistochemical expression of different subtypes of cytokeratins by endometrial stromal sarcoma. Appl Immunohistochem Mol Morphol 2019; 27(6): 466-470.

66. Yilmaz A, Rush DS, Soslow RA. Endometrial stromal sarcomas with unusual histologic features: A report of 24 primary and metastatic tumors emphasizing fibroblastic and smooth muscle differentiation. Am J Surg Pathol 2002; 26(9): 1142-1150.

67. Dundr P, Fischerová D, Povýšil C, Cibula D, Zikan M. Myxoid mixed low-grade endometrial stromal sarcoma and smooth muscle tumor of the uterus. Case report. Cesk Patol 2012; 48(2): 103-106.

68. Davidson B, Micci F. Molecular characteristics of uterine sarcomas. Expert Rev Mol Diagn 2017; 17(5): 515-522.

69. Sreekantaiah C, Li FP, Weidner N, Sandberg AA. An endometrial stromal sarcoma with clonal cytogenetic abnormalities. Cancer Genet Cytogenet 1991; 55(2): 163-166.

70. Koontz JI, Soreng AL, Nucci M, et al. Frequent fusion of the jazf1 and jjaz1 genes in endometrial stromal tumors. Proc Natl Acad Sci U S A 2001; 98(11): 6348-6353.

71. Micci F, Panagopoulos I, Bjerkehagen B, Heim S. Consistent rearrangement of chromosomal band 6p21 with generation of fusion genes jazf1/phf1 and epc1/phf1 in endometrial stromal sarcoma. Cancer Res 2006; 66(1): 107-112.

72. Dewaele B, Przybyl J, Quattrone A, et al. Identification of a novel, recurrent mbtd1-cxorf67 fusion in low-grade endometrial stromal sarcoma. Int J Cancer 2014; 134(5): 1112-1122.

73. Panagopoulos I, Thorsen J, Gorunova L, et al. Fusion of the zc3h7b and bcor genes in endometrial stromal sarcomas carrying an x;22-translocation. Genes Chromosomes Cancer 2013; 52(7): 610-618.

74. Hoang LN, Aneja A, Conlon N, et al. Novel high-grade endometrial stromal sarcoma: A morphologic mimicker of myxoid leiomyosarcoma. Am J Surg Pathol 2017; 41(1): 12-24.

75. Ondic O, Bednarova B, Ptakova N, et al. ZC3H7B-BCOR high-grade endometrial stromal sarcoma may present as myoma nascens with cytoplasmic signet ring cell change. Virchows Arch 2020; 476(4): 615-619.

76. Chiang S, Ali R, Melnyk N, et al. Frequency of known gene rearrangements in endometrial stromal tumors. Am J Surg Pathol 2011; 35(9): 1364-1372.

77. Micci F, Gorunova L, Agostini A, et al. Cytogenetic and molecular profile of endometrial stromal sarcoma. Genes Chromosomes Cancer 2016; 55(11): 834-846.

78. Kolin DL, Dong F, Baltay M, et al. Smarca4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): A clinicopathologic entity distinct from undifferentiated carcinoma. Mod Pathol 2018; 31(9): 1442-1456.

79. Lin DI, Allen JM, Hecht JL, et al. SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association. Mod Pathol 2019; 32(11):1675-1687.

80. Mccluggage WG, Lee CH. YWHAE-NUTM2A/B translocated high-grade endometrial stromal sarcoma commonly expresses cd56 and cd99. Int J Gynecol Pathol 2019; 38(6): 528-532.

81. Shah VI, Mccluggage WG. Cyclin D1 does not distinguish YWHAE-NUTM2 high-grade endometrial stromal sarcoma from undifferentiated endometrial carcinoma. Am J Surg Pathol 2015; 39(5): 722-724.

82. Kao YC, Sung YS, Zhang L, et al. Recurrent bcor internal tandem duplication and ywhae-nutm2b fusions in soft tissue undifferentiated round cell sarcoma of infancy: Overlapping genetic features with clear cell sarcoma of kidney. Am J Surg Pathol 2016; 40(8): 1009-1020.

83. Mansor S, Kuick CH, Lim SL, et al. ZC3H7B-BCOR-rearranged endometrial stromal sarcomas: A distinct subset merits its own classification? Int J Gynecol Pathol 2018;

84. Marino-Enriquez A, Lauria A, Przybyl J, et al. BCOR internal tandem duplication in high-grade uterine sarcomas. Am J Surg Pathol 2018; 42(3): 335-341.

85. Chiang S, Cotzia P, Hyman DM, et al. NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma. Am J Surg Pathol 2018; 42(6): 791-798.

86. Lee CH, Ali RH, Rouzbahman M, et al. Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE-FAM22 rearrangement. Am J Surg Pathol 2012; 36(10): 1562-1570.

87. Lee CH, Marino-Enriquez A, Ou W, et al. The clinicopathologic features of YWHAE-FAM22 endometrial stromal sarcomas: A histologically high-grade and clinically aggressive tumor. Am J Surg Pathol 2012; 36(5): 641-653.

88. Lee CH, Hoang LN, Yip S, et al. Frequent expression of kit in endometrial stromal sarcoma with ywhae genetic rearrangement. Mod Pathol 2014; 27(5): 751-757.

89. Isphording A, Ali RH, Irving J, et al. Ywhae-fam22 endometrial stromal sarcoma: Diagnosis by reverse transcription-polymerase chain reaction in formalin-fixed, paraffin-embedded tumor. Hum Pathol 2013; 44(5): 837-843.

90. Lewis N, Soslow RA, Delair DF, et al. ZC3H7B-BCOR high-grade endometrial stromal sarcomas: A report of 17 cases of a newly defined entity. Mod Pathol 2018; 31(4): 674-684.

91. Mills AM, Karamchandani JR, Vogel H, Longacre TA. Endocervical fibroblastic malignant peripheral nerve sheath tumor (neurofibrosarcoma): Report of a novel entity possibly related to endocervical CD34 fibrocytes. Am J Surg Pathol 2011; 35(3): 404-412.

92. Kurihara S, Oda Y, Ohishi Y, et al. Endometrial stromal sarcomas and related high-grade sarcomas: Immunohistochemical and molecular genetic study of 31 cases. Am J Surg Pathol 2008; 32(8): 1228-1238.

93. Bartosch C, Exposito MI, Lopes JM. Low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma: A comparative analysis emphasizing the importance of distinguishing between these two groups. Int J Surg Pathol 2010; 18(4): 286-291.

94. Jakate K, Azimi F, Ali RH, et al. Endometrial sarcomas: An immunohistochemical and JAZF1 re-arrangement study in low-grade and undifferentiated tumors. Mod Pathol 2013; 26(1): 95-105.

95. Sciallis AP, Bedroske PP, Schoolmeester JK, et al. High-grade endometrial stromal sarcomas: A clinicopathologic study of a group of tumors with heterogenous morphologic and genetic features. Am J Surg Pathol 2014; 38(9): 1161-1172.

96. Stikova Z, Ptakova N, Horakova M, Kostun J, Ondic O. Inflammatory myofibroblastic tumor of the uterus - case report. Cesk Patol 2019; 55(4): 239-243.

97. Bennett JA, Nardi V, Rouzbahman M, et al. Inflammatory myofibroblastic tumor of the uterus: A clinicopathological, immunohistochemical, and molecular analysis of 13 cases highlighting their broad morphologic spectrum. Mod Pathol 2017; 30(10): 1489-1503.

98. Shukla PS, Mittal K. Inflammatory myofibroblastic tumor in female genital tract. Arch Pathol Lab Med 2019; 143(1): 122-129.