Skip to main content

Advertisement

SpringerLink
Log in

Epithelioid fibrous histiocytoma: three diagnostically challenging cases with novel ALK gene fusions, unusual storiform growth pattern, and a prominent spindled morphology

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract 

Epithelioid fibrous histiocytoma (EFH) is a distinctive cutaneous neoplasm with a relatively variable morphological appearance. Recently, it has been shown that this tumor is molecularly characterized by ALK gene fusions. We report three EFHs with unusual histological presentation represented by a prominent/predominant spindle cell proliferation arranged in a variably storiform/whirling architectural pattern with or without stromal sclerosis. One of the cases closely resembled cellular fibrous histiocytoma. All three cases were immunohistochemically ALK-positive and were analyzed for ALK gene rearrangements using a next-generation sequencing–based assay (FusionPlex Sarcoma Kit, ArcherDx). Three novel fusions, namely AP3D1::ALK, COL1A::ALK, and LRRFIP2::ALK, were detected and further confirmed by FISH in all 3 cases and RT-PCR in 1 case. All patients were elderly (62–63 years) and presented with a solitary polypoid lesion on the extremities. The awareness of these morphological variants is important since it entertains a wide and slightly different differential diagnosis than conventional EFH. We also presented evidence that a clear separation of EFH from BFH in all cases may not be as straightforward as previously thought. The consistent ALK immunoexpression and the continually expanding scale of ALK gene rearrangements provide a useful tool to distinguish EFH from its histologic mimics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Jones EW, Cerio R, Smith NP (1989) Epithelioid cell histiocytoma: a new entity. Br J Dermatol 120:185–195

    Article  CAS  PubMed  Google Scholar 

  2. Kazakov DV, Kyrpychova L, Martinek P et al (2018) ALK gene fusions in epithelioid fibrous histiocytoma: a study of 14 cases, with new histopathological findings. Am J Dermatopathol 1–10

  3. Doyle LA, Marino-Enriquez A, Fletcher CD, Hornick JL (2015) ALK rearrangement and overexpression in epithelioid fibrous histiocytoma. Mod Pathol 28(7):904–912

    Article  CAS  PubMed  Google Scholar 

  4. Dickson BC, Swanson D, Charames GS et al (2018) Epithelioid fibrous histiocytoma: molecular characterization of ALK fusion partners in 23 cases. Mod Pathol 31:753–762

    Article  CAS  PubMed  Google Scholar 

  5. Georgantzoglou N, Green D, Winnick KN et al (2022) Molecular investigation of ALK-rearranged epithelioid fibrous histiocytomas identifies CLTC as a novel fusion partner and evidence of fusion-independent transcription activation. Genes Chromosom Cancer 1‐10

  6. Gomez CS, Calonje E, Fletcher C (1994) Epithelioid benign fibrous histiocytoma of skin: clinico-pathological analysis of 20 cases of a poorly known variant. Histopathology 24:123–129

    Article  Google Scholar 

  7. Glusac EJ, McNiff JM (1999) Epithelioid cell histiocytoma: a simulant of vascular and melanocytic neoplasms. Am J Dermatopathol 21:1–7

    Article  CAS  PubMed  Google Scholar 

  8. Jedrych J, Nikiforova M, Kennedy TF et al (2015) Epithelioid cell histiocytoma of the skin with clonal ALK gene rearrangement resulting in VCL-ALK and SQSTM1-ALK gene fusions. Br J Dermatol 172:1427–1429

    Article  CAS  PubMed  Google Scholar 

  9. Miura Y, Misago N, Narisawa Y (2005) Epithelioid cell histiocytoma with underlying artery damage. J Dermatol 32:721–726

    Article  PubMed  Google Scholar 

  10. Murigu T, Bhatt N, Miller K, Palmer A, Melegh Z (2018) Spindle cell predominant epithelioid fibrous histiocytoma. Histopathology 72(7):1233–1236

    Article  PubMed  Google Scholar 

  11. Lee J (2007) Epithelioid cell histiocytoma with granular cells (another nonneural granular cell neoplasm). Am J Dermatopathol 29(5):475–476

    Article  PubMed  Google Scholar 

  12. Martinez AP, Zou Y, Billings SD et al (2018) “Chondroblastoma-like” epithelioid fibrous histiocytoma: a previously undescribed and potentially confusing variant. J Cutan Pathol 45:99–103

    Article  PubMed  Google Scholar 

  13. Creytens D, Ferdinande L, Van Dorpe J (2017) ALK rearrangement and overexpression in an unusual cutaneous epithelioid tumor with a peculiar whorled “perineurioma-like” growth pattern: epithelioid fibrous histiocytoma. Appl Immunohistochem Mol Morphol 25:e48

    Article  Google Scholar 

  14. Chang KTE, Tay AZE, Kuick CH, Chen H, Algar E, Taubenheim N, Campbell J, Mechinaud F, Campbell M, Super L, Chantranuwat C, Yuen ST, Chan JKC, Chow CW (2019) ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion. Mod Pathol 32(5):598–608

    Article  PubMed  Google Scholar 

  15. WHO (2018) Classification of Skin Tumours. 4th ed. Lyon, France: World Health Organization

  16. Płaszczyca A, Nilsson J, Magnusson L, Brosjö O, Larsson O, Vult von Steyern F, Domanski HA, Lilljebjörn H, Fioretos T, Tayebwa J, Mandahl N, Nord KH, Mertens F (2014) Fusions involving protein kinase C and membrane-associated proteins in benign fibrous histiocytoma. Int J Biochem Cell Biol 53:475–81

    Article  PubMed  Google Scholar 

  17. Walther C, Hofvander J, Nilsson J, Magnusson L, Domanski HA, Gisselsson D, Tayebwa J, Doyle LA, Fletcher CD, Mertens F (2015) Gene fusion detection in formalin-fixed paraffin-embedded benign fibrous histiocytomas using fluorescence in situ hybridization and RNA sequencing. Lab Invest 95(9):1071–1076

    Article  CAS  PubMed  Google Scholar 

  18. Panagopoulos I, Gorunova L, Bjerkehagen B, Lobmaier I, Heim S (2015) LAMTOR1-PRKCD and NUMA1-SFMBT1 fusion genes identified by RNA sequencing in aneurysmal benign fibrous histiocytoma with t(3;11)(p21;q13). Cancer Genet 208(11):545–551

    Article  CAS  PubMed  Google Scholar 

  19. Dermawan JK, Azzato EM, Goldblum JR, Rubin BP, Billings SD, Ko JS (2021) Superficial ALK-rearranged myxoid spindle cell neoplasm: a cutaneous soft tissue tumor with distinctive morphology and immunophenotypic profile. Mod Pathol 34(9):1710–1718

    Article  CAS  PubMed  Google Scholar 

  20. Rapini RP, Golitz LE (1989) Sclerotic fibromas of the skin. J Am Acad Dermatol 20(2 Pt 1):266–271

    Article  CAS  PubMed  Google Scholar 

  21. Pujol RM, de Castro F, Schroeter AL, Su WP (1996) Solitary sclerotic fibroma of the skin: a sclerotic dermatofibroma? Am J Dermatopathol 18(6):620–624

    Article  CAS  PubMed  Google Scholar 

  22. Fetsch JF, Miettinen M (1997) Sclerosing perineurioma: a clinicopathologic study of 19 cases of a distinctive soft tissue lesion with a predilection for the fingers and palms of young adults. Am J Surg Pathol 21(12):1433–1442

    Article  CAS  PubMed  Google Scholar 

  23. Robson AM, Calonje E (2000) Cutaneous perineurioma: a poorly recognized tumour often misdiagnosed as epithelioid histiocytoma. Histopathology 37(4):332–339

    Article  CAS  PubMed  Google Scholar 

  24. Doyle LA, Fletcher CD (2011) EMA positivity in epithelioid fibrous histiocytoma: a potential diagnostic pitfall. J Cutan Pathol 38(9):697–703

    Article  PubMed  Google Scholar 

  25. Folpe AL, Billings SD, McKenney JK, Walsh SV, Nusrat A, Weiss SW (2002) Expression of claudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from potential mimics. Am J Surg Pathol 26(12):1620–1626

    Article  PubMed  Google Scholar 

  26. Hirose T, Tani T, Shimada T, Ishizawa K, Shimada S, Sano T (2003) Immunohistochemical demonstration of EMA/Glut1-positive perineurial cells and CD34-positive fibroblastic cells in peripheral nerve sheath tumors. Mod Pathol 16(4):293–298

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  29. Lau PP, Lui PC, Lau GT, Yau DT, Cheung ET, Chan JK (2013) EWSR1-CREB3L1 gene fusion: a novel alternative molecular aberration of low-grade fibromyxoid sarcoma. Am J Surg Pathol 37(5):734–738

    Article  PubMed  Google Scholar 

  30. LeBoit PE, Yen TS, Wintroub B (1986) The evolution of lesions in erythema elevatum diutinum. Am J Dermatopathol 8(5):392–402

    Article  CAS  PubMed  Google Scholar 

  31. Yiannias JA, el-Azhary RA, Gibson LE (1992) Erythema elevatum diutinum a clinical and histopathologic study of 13 patients. J Am Acad Dermatol 26(1):38–44

    Article  CAS  PubMed  Google Scholar 

  32. High WA, Hoang MP, Stevens K, Cockerell CJ (2003) Late-stage nodular erythema elevatum diutinum. J Am Acad Dermatol 49(4):764–767

    Article  PubMed  Google Scholar 

  33. Mariño-Enríquez A, Dal Cin P (2013) ALK as a paradigm of oncogenic promiscuity: different mechanisms of activation and different fusion partners drive tumors of different lineages. Cancer Genet 206(11):357–373

    Article  PubMed  Google Scholar 

  34. Mohammed M, Al-Hashmi N, Al-Rashdi S, Al-Sukaiti N, Al-Adawi K, Al-Riyami M, Al-Maawali A (2019) Biallelic mutations in AP3D1 cause Hermansky-Pudlak syndrome type 10 associated with immunodeficiency and seizure disorder. Eur J Med Genet 62(11):103583

    Article  PubMed  Google Scholar 

  35. Ammann S, Schulz A, Krägeloh-Mann I et al (2016) Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood 127(8):997–1006

    Article  CAS  PubMed  Google Scholar 

  36. Liu J, Bang AG, Kintner C, Orth AP, Chanda SK, Ding S, Schultz PG (2005) Identification of the Wnt signaling activator leucine-rich repeat in Flightless interaction protein 2 by a genome-wide functional analysis. Proc Natl Acad Sci USA 102(6):1927–1932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dai P, Jeong SY, Yu Y, Leng T, Wu W, Xie L, Chen X (2009) Modulation of TLR signaling by multiple MyD88-interacting partners including leucine-rich repeat Fli-I-interacting proteins. J Immunol 182(6):3450–3460

    Article  CAS  PubMed  Google Scholar 

  38. Jin J, Yu Q, Han C et al (2013) LRRFIP2 negatively regulates NLRP3 inflammasome activation in macrophages by promoting flightless-Imediated caspase-1 inhibition. Nat Commun 4:20

    Article  Google Scholar 

  39. Pinheiro M, Pinto C, Peixoto A et al (2011) A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families. Genet Med 13(10):895–902

    Article  CAS  PubMed  Google Scholar 

  40. Dalgleish R (1997) The human type I collagen mutation database. Nucleic Acids Res 25(1):181–187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hwang SJ, Ha GH, Seo WY, Kim CK, Kim K, Lee SB (2020) Human collagen alpha-2 type I stimulates collagen synthesis, wound healing, and elastin production in normal human dermal fibroblasts (HDFs). BMB Rep 53(10):539–544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University Hospital Campus Bio-Medico, Rome, Italy

    Boulos Mansour & Michele Donati

  2. Bioptical Laboratory, Ltd., Pilsen, Czech Republic

    Květoslava Michalová, Michal Michal, Nikola Ptáková, Veronika Hájková & Michael Michal

  3. Department of Pathology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic

    Květoslava Michalová, Michal Michal & Michael Michal

Authors
  1. Boulos Mansour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michele Donati
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Květoslava Michalová
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michal Michal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nikola Ptáková
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Veronika Hájková
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Michal
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization and writing the original draft preparation: MB. Writing—review and editing: DM, MM, and MM. Project the manuscript: MM. All authors have read and agreed to the submitted version of the manuscript.

Corresponding author

Correspondence to Boulos Mansour.

Ethics declarations

Ethics approval

N/A.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mansour, B., Donati, M., Michalová, K. et al. Epithelioid fibrous histiocytoma: three diagnostically challenging cases with novel ALK gene fusions, unusual storiform growth pattern, and a prominent spindled morphology. Virchows Arch 481, 751–757 (2022). https://doi.org/10.1007/s00428-022-03418-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-022-03418-0

Keywords

Search

Navigation