An update on immunohistochemical and molecular genetic markers of selected soft tissue tumors

Czech version

Authors: Michael Michal ^1,2
Authors‘ workplace: Bioptická laboratoř, s. r. o., Plzeň ¹; Šiklův ústav patologie LF UK v Plzni a FN Plzeň ²
Published in: Čes.-slov. Patol., 57, 2021, No. 1, p. 19-29
Category: Reviews Article

Overview

Recent years have brought an immense increase of knowledge regarding the molecular genetic background of mesenchymal tumors which in turn has significantly expanded the repertoire of molecular markers available for the routine diagnostic practice. This progress has also been followed by a rising number of available immunohistochemical markers useful for the diagnosis of soft tissue neoplasia. Both lineage specific and tumor-specific immunohistochemical antibodies have been discovered and subsequently tested in the surgical pathology practice. This article will review some of the immunohistochemical and molecular genetic markers useful in the diagnosis of vascular tumors, malignant peripheral nerve sheath tumors, low-grade fibromyxoid sarcomas/sclerosing epithelioid fibrosarcomas, solitary fibrous tumors, epithelioid sarcomas, rhabdomyosarcomas and other lesions showing skeletal muscle differentiation. The immunohistochemical and molecular genetic features of some recently characterized and clinically particularly important entities will be discussed as well.

Keywords:

soft tissue neoplasia – mesenchymal tumors – immunohistochemistry – Molecular genetics

Sources

1. Kinkor Z, Grossmann P, Dubová M, et al. Co nového v Ewing-like family aneb malobuněčné/kulatobuněčné sarkomy měkkých tkání a kostí s rearanží genu CIC a BCOR. Přehled problematiky a naše prvotní zkušenosti. Cesk Patol; 53(4): 175-180.

2. Michal M, Kazakov DV, Michal M. Hybrid peripheral nerve sheath tumors: a review. Cesk Patol; 53(2): 81-88.

3. Švajdler M, Zambo I, Michal M, Kinkor Z, Michal M. Nádory měkkých tkání. Doporučený postup pro bioptické vyšetření. Společnost českých patologů, ČSL JEP, 2019.http://www.patologie.info/soubory/all/2018-4_Guideline-web-v1.pdf

4. Wang NP, Marx J, McNutt MA, Rutledge JC, Gown AM. Expression of myogenic regulatory proteins (myogenin and MyoD1) in small blue round cell tumors of childhood. Am J Pathol 1995; 147(6): 1799-1810.

5. Morotti RA, Nicol KK, Parham DM, et al. An immunohistochemical algorithm to facilitate diagnosis and subtyping of rhabdomyosarcoma: the Children’s Oncology Group experience. Am J Surg Pathol 2006; 30(8): 962-968.

6. Dias P, Chen B, Dilday B, et al. Strong immunostaining for myogenin in rhabdomyosarcoma is significantly associated with tumors of the alveolar subclass. Am J Pathol 2000; 156(2): 399-408.

7. Charville GW, Varma S, Forgo E, et al. PAX7 expression in rhabdomyosarcoma, related soft tissue tumors, and small round blue cell neoplasms. Am J Surg Pathol 2016; 40(10): 1305-1315.

8. Charville GW, Wang WL, Ingram DR, et al. EWSR1 fusion proteins mediate PAX7 expression in Ewing sarcoma. Mod Pathol 2017; 30(9): 1312-1320.

9. Leiner J, Le Loarer F. The current landscape of rhabdomyosarcomas: an update. Virchows Arch 2020; 476(1): 97-108.

10. Borinstein SC, Steppan D, Hayashi M, et al. Consensus and controversies regarding the treatment of rhabdomyosarcoma. Pediatr Blood Cancer 2018; 65(2): 10.1002/pbc.26809.

11. Alaggio R, Zhang L, Sung YS, et al. A molecular study of pediatric spindle and sclerosing rhabdomyosarcoma: identification of novel and recurrent VGLL2-related fusions in infantile cases. Am J Surg Pathol 2016; 40(2): 224-235.

12. Le Loarer F, Cleven AHG, Bouvier C, et al. A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation. Mod Pathol2020; 33(3): 404-419.

13. Brunac AC, Laprie A, Castex MP, et al. The combination of radiotherapy and ALK inhibitors is effective in the treatment of intraosseous rhabdomyosarcoma with FUS-TFCP2 fusion transcript. Pediatr Blood Cancer 2020: e28185.

14. Michal M, Rubin BP, Kazakov DV, et al. Inflammatory leiomyosarcoma shows frequent co-expression of smooth and skeletal muscle markers supporting a primitive myogenic phenotype: a report of 9 cases with a proposal for reclassification as low-grade inflammatory myogenic tumor. Virchows Arch. In press 2020.

15. Martinez AP, Fritchie KJ, Weiss SW, et al. Histiocyte-rich rhabdomyoblastic tumor: rhabdomyosarcoma, rhabdomyoma, or rhabdomyoblastic tumor of uncertain malignant potential? A histologically distinctive rhabdomyoblastic tumor in search of a place in the classification of skeletal muscle neoplasms. Mod Pathol 2019; 32(3): 446-457.

16. Merchant W, Calonje E, Fletcher CD. Inflammatory leiomyosarcoma: a morphological subgroup within the heterogeneous family of so-called inflammatory malignant fibrous histiocytoma. Histopathology 1995; 27(6): 525-532.

17. Bridge JA, Sumegi J, Druta M, et al. Clinical, pathological, and genomic features of EWSR1-PATZ1 fusion sarcoma. Mod Pathol 2019; 32(11): 1593-1604.

18. Chougule A, Taylor MS, Nardi V, et al. Spindle and round cell sarcoma with EWSR1-PATZ1 gene fusion: asarcoma with polyphenotypic differentiation. Am J Surg Pathol 2019; 43(2): 220-228.

19. Folpe AL, Graham RP, Martinez A, Schembri-Wismayer D, Boland J, Fritchie KJ. Mesenchymal chondrosarcomas showing immunohistochemical evidence of rhabdomyoblastic differentiation: a potential diagnostic pitfall. Hum Pathol 2018; 77: 28-34.

20. Patel RM, Goldblum JR, Hsi ED. Immunohistochemical detection of human herpes virus-8 latent nuclear antigen-1 is useful in the diagnosis of Kaposi sarcoma. Mod Pathol 2004; 17(4): 456-460.

21. Hammock L, Reisenauer A, Wang W, Cohen C, Birdsong G, Folpe AL. Latency-associated nuclear antigen expression and human herpesvirus-8 polymerase chain reaction in the evaluation of Kaposi sarcoma and other vascular tumors in HIV-positive patients. Mod Pathol 2005; 18(4): 463-468.

22. Ordonez NG. Immunohistochemical endothelial markers: a review. Adv Anat Pathol 2012; 19(5): 281-295.

23. Miettinen M, Wang ZF, Paetau A, et al. ERG transcription factor as an immunohistochemical marker for vascular endothelial tumors and prostatic carcinoma. Am J Surg Pathol 2011; 35(3): 432-441.

24. Stockman DL, Hornick JL, Deavers MT, Lev DC, Lazar AJ, Wang WL. ERG and FLI1 protein expression in epithelioid sarcoma. Mod Pathol 2014; 27(4): 496-501.

25. Shon W, Folpe AL, Fritchie KJ. ERG expression in chondrogenic bone and soft tissue tumours. J Clin Pathol 2015; 68(2): 125-129.

26. Creytens D. ERG expression in chondrogenic bone and soft tissue tumours: importance of antibody clone. Comment on Shon et al (2015). J Clin Pathol 2015; 68(12): 1043.

27. Xu B, Naughton D, Busam K, Pulitzer M. ERG is a useful immunohistochemical marker to distinguish leukemia cutis from nonneoplastic leukocytic infiltrates in the skin. Am J Dermatopathol 2016; 38(9): 672-677.

28. Wang WL, Patel NR, Caragea M, et al. Expression of ERG, an Ets family transcription factor, identifies ERG-rearranged Ewing sarcoma. Mod Pathol 2012; 25(10): 1378-1383.

29. Chaux A, Albadine R, Toubaji A, et al. Immunohistochemistry for ERG expression as a surrogate for TMPRSS2-ERG fusion detection in prostatic adenocarcinomas. Am J Surg Pathol 2011; 35(7): 1014-1020.

30. Agaimy A, Michal M, Chiosea S, et al. Phosphaturic mesenchymal tumors: clinicopathologic, immunohistochemical and molecular analysis of 22 cases expanding their morphologic and immunophenotypic spectrum. Am J Surg Pathol 2017; 41(10): 1371-1380.

31. Kao YC, Flucke U, Eijkelenboom A, et al. Novel EWSR1-SMAD3 Gene Fusions in a Group of Acral Fibroblastic Spindle Cell Neoplasms. Am J Surg Pathol 2018; 42: 522-528.

32. Michal M, Berry RS, Rubin BP, et al. EWSR1-SMAD3-rearranged fibroblastic tumor: an emerging entity in an increasingly more complex group of fibroblastic/myofibroblastic neoplasms. Am J Surg Pathol 2018; 42(4): 1325-1333.

33. McKenney JK, Weiss SW, Folpe AL. CD31 expression in intratumoral macrophages: a potential diagnostic pitfall. Am J Surg Pathol 2001; 25(9): 1167-1173.

34. Slone SP, Fleming DR, Buchino JJ. Sinus histiocytosis with massive lymphadenopathy and Langerhans cell histiocytosis express the cellular adhesion molecule CD31. Arch Pathol Lab Med 2003; 127(3): 341-344.

35. Vanchinathan V, Mirzamani N, Kantipudi R, Schwartz EJ, Sundram UN. The vascular marker CD31 also highlights histiocytes and histiocyte-like cells within cutaneous tumors. Am J Clin Pathol 2015; 143(2): 177-185; quiz 305.

36. Xu Y, Ogose A, Kawashima H, et al. High-level expression of podoplanin in benign and malignant soft tissue tumors: immunohistochemical and quantitative real-time RT-PCR analysis. Oncol Rep 2011; 25(3): 599-607.

37. Miettinen M, Wang ZF. Prox1 transcription factor as a marker for vascular tumors-evaluation of 314 vascular endothelial and 1086 nonvascular tumors. Am J Surg Pathol 2012; 36(3): 351-359.

38. Husain AN, Colby TV, Ordonez NG, et al. Guidelines for pathologic diagnosis of malignant mesothelioma 2017 update of the consensus statement from the international mesothelioma interest group. Arch Pathol Lab Med 2018; 142(1): 89-108.

39. Hung YP, Fletcher CD, Hornick JL. FOSB is a useful diagnostic marker for pseudomyogenic hemangioendothelioma. Am J Surg Pathol 2017; 41(5): 596-606.

40. Billings SD, Folpe AL, Weiss SW. Epithelioid sarcoma-like hemangioendothelioma. Am J Surg Pathol 2003; 27(1): 48-57.

41. Agaram NP, Zhang L, Cotzia P, Antonescu CR. Expanding the spectrum of genetic alterations in pseudomyogenic hemangioendothelioma with recurrent novel ACTB-FOSB gene fusions. Am J Surg Pathol 2018; 42(12): 1653-1661.

42. Tanas MR, Sboner A, Oliveira AM, et al. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci Transl Med 2011; 3(98): 98ra82.

43. Shibuya R, Matsuyama A, Shiba E, Harada H, Yabuki K, Hisaoka M. CAMTA1 is a useful immunohistochemical marker for diagnosing epithelioid haemangioendothelioma. Histopathology 2015; 67(6): 827-835.

44. Antonescu CR, Le Loarer F, Mosquera JM, et al. Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer 2013; 52(8): 775-784.

45. Sharain RF, Gown AM, Greipp PT, Folpe AL. Immunohistochemistry for TFE3 lacks specificity and sensitivity in the diagnosis of TFE3-rearranged neoplasms: a comparative, 2-laboratory study. Hum Pathol 2019; 87: 65-74.

46. Habeeb O, Rubin BP. The molecular diagnostics of vascular neoplasms. Surg Pathol Clin 2019; 12(1): 35-49.

47. North PE, Waner M, James CA, Mizeracki A, Frieden IJ, Mihm MC, Jr. Congenital nonprogressive hemangioma: a distinct clinicopathologic entity unlike infantile hemangioma. Arch Dermatol 2001; 137(12): 1607-1620.

48. North PE, Waner M, Mizeracki A, Mihm MC, Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000; 31(1): 11-22.

49. Hornick JL, Dal Cin P, Fletcher CD. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol 2009; 33(4): 542-550.

50. Schaefer IM, Dong F, Garcia EP, Fletcher CDM, Jo VY. Recurrent SMARCB1 inactivation in epithelioid malignant peripheral nerve sheath tumors. Am J Surg Pathol 2019; 43(6): 835-843.

51. Jo VY, Fletcher CDM. SMARCB1/INI1 loss in epithelioid schwannoma: aclinicopathologic and immunohistochemical study of 65 Cases. Am J Surg Pathol 2017; 41(8): 1013-1022.

52. Agaimy A. The expanding family of SMARCB1(INI1)-deficient neoplasia: implications of phenotypic, biological, and molecular heterogeneity. Adv Anat Pathol 2014; 21(6): 394-410.

53. Švajdler M, Michal M, Martínek P, et al. Fibro-osseous pseudotumor of digits and myositis ossificans show consistent COL1A1-USP6 rearrangement: a clinicopathological and genetic study of 27 cases. Hum Pathol 2019; 88: 39-47.

54. Oliveira AM, Chou MM. USP6-induced neoplasms: the biologic spectrum of aneurysmal bone cyst and nodular fasciitis. Hum Pathol 2014; 45(1): 1-11.

55. Kasashima S, Kawashima A, Zen Y, et al. Expression of aberrant mucins in lobular carcinoma with histiocytoid feature of the breast. Virchows Arch 2007; 450(4): 397-403.

56. Meis-Kindblom JM, Kindblom LG, Enzinger FM. Sclerosing epithelioid fibrosarcoma. A variant of fibrosarcoma simulating carcinoma. Am J Surg Pathol 1995; 19(9): 979-993.

57. Doyle LA, Wang WL, Dal Cin P, et al. MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma: association with FUS gene rearrangement. Am J Surg Pathol 2012; 36(10): 1444-1451.

58. Kao YC, Lee JC, Zhang L, et al. Recurrent YAP1 and KMT2A gene rearrangements in a subset of MUC4-negative sclerosing epithelioid fibrosarcoma. Am J Surg Pathol 2020; 44(3): 368-377.

59. Puls F, Agaimy A, Flucke U, et al. Recurrent fusions between YAP1 and KMT2A in morphologically distinct neoplasms within the spectrum of low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma. Am J Surg Pathol. In press 2020.

60. Evans HL. Low-grade fibromyxoid sarcoma: a clinicopathologic study of 33 cases with long-term follow-up. Am J Surg Pathol 2011; 35(10): 1450-1462.

61. Folpe AL, Lane KL, Paull G, Weiss SW. Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: a clinicopathologic study of 73 cases supporting their identity and assessing the impact of high-grade areas. Am J Surg Pathol 2000; 24(10): 1353-1360.

62. Doyle LA, Moller E, Dal Cin P, Fletcher CD, Mertens F, Hornick JL. MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am J Surg Pathol 2011; 35(5): 733-741.

63. Abrahao-Machado LF, Bacchi LM, Fernandes IL, Costa FD, Bacchi CE. MUC4 expression in angiomatoid fibrous histiocytoma. Appl Immunohistochem Mol Morphol. In press 2019.

64. Matsuyama A, Jotatsu M, Uchihashi K, et al. MUC4 expression in meningiomas: under-recognized immunophenotype particularly in meningothelial and angiomatous subtypes. Histopathology 2019; 74(2): 276-283.

65. Davis JL, Lockwood CM, Stohr B, et al. Expanding the spectrum of pediatric NTRK-rearranged mesenchymal tumors. Am J Surg Pathol 2019; 43(4): 435-445.

66. Kao YC, Fletcher CDM, Alaggio R, et al. Recurrent BRAF gene fusions in a subset of pediatric spindle cell sarcomas: expanding the genetic spectrum of tumors with overlapping features with infantile fibrosarcoma. Am J Surg Pathol 2018; 42(1): 28-38.

67. Suurmeijer AJH, Dickson BC, Swanson D, et al. A novel group of spindle cell tumors defined by S100 and CD34 co-expression shows recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes. Genes Chromosomes Cancer 2018; 57(12): 611-621.

68. Antonescu CR, Dickson BC, Swanson D, et al. Spindle cell tumors with RET gene fusions exhibit a morphologic spectrum akin to tumors with NTRK gene fusions. Am J Surg Pathol 2019; 43(10): 1384-1391.

69. Michal M, Ptáková N, Martínek P, et al. S100 and CD34 positive spindle cell tumor with prominent perivascular hyalinization and a novel NCOA4-RET fusion. Genes Chromosomes Cancer 2019; 58(9): 680-685.

70. Agaram NP, Zhang L, Sung YS, et al. Recurrent NTRK1 gene fusions define a novel subset of locally aggressive lipofibromatosis-like neural tumors. Am J Surg Pathol 2016; 40(10): 1407-1416.

71. Schaefer IM, Fletcher CD, Hornick JL. Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. Mod Pathol 2016; 29(1): 4-13.

72. Cleven AH, Sannaa GA, Briaire-de Bruijn I, et al. Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival. Mod Pathol 2016; 29(6): 582-590.

73. Pekmezci M, Reuss DE, Hirbe AC, et al. Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas. Mod Pathol 2015; 28(2): 187-200.

74. Marchione DM, Lisby A, Viaene AN, et al. Histone H3K27 dimethyl loss is highly specific for malignant peripheral nerve sheath tumor and distinguishes true PRC2 loss from isolated H3K27 trimethyl loss. Mod Pathol 2019; 32(10): 1434-1446.

75. Carter JM, Weiss SW, Linos K, DiCaudo DJ, Folpe AL. Superficial CD34-positive fibroblastic tumor: report of 18 cases of a distinctive low-grade mesenchymal neoplasm of intermediate (borderline) malignancy. Mod Pathol 2014; 27(2): 294-302.

76. Lao IW, Yu L, Wang J. Superficial CD34-positive fibroblastic tumour: a clinicopathological and immunohistochemical study of an additional series. Histopathology 2017; 70(3): 394-401.

77. Puls F, Pillay N, Fagman H, et al. PRDM10-rearranged soft tissue tumor: aclinicopathologic study of 9 cases. Am J Surg Pathol 2019; 43(4): 504-513.

78. Robinson DR, Wu YM, Kalyana-Sundaram S, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet 2013; 45(2): 180-185.

79. Chmielecki J, Crago AM, Rosenberg M, et al. Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet 2013; 45(2): 131-132.

80. Demicco EG, Harms PW, Patel RM, et al. Extensive survey of STAT6 expression in a large series of mesenchymal tumors. Am J Clin Pathol 2015; 143(5): 672-682.

81. Doyle LA, Vivero M, Fletcher CD, Mertens F, Hornick JL. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol 2014; 27(3): 390-395.

82. Dagrada GP, Spagnuolo RD, Mauro V, et al. Solitary fibrous tumors: loss of chimeric protein expression and genomic instability mark dedifferentiation. Mod Pathol 2015; 28(8): 1074-1083.