Intravascular epithelioid haemangioma of deep soft tissue with novel SETD1B-FOSB gene rearrangement

Abstract

Epithelioid vascular neoplasms encompass a spectrum of benign to malignant entities that can show overlapping morphological features, belying significant differences in biological behaviour.1Fletcher C.D.M. Bridge J.A. Hogendoorn P.C.W. et al.World Health Organization Classification of Tumours of Soft Tissue and Bone.4th ed. IARC Press, Lyon2013Google Scholar In recent years, the molecular underpinnings of several epithelioid vascular neoplasms have been delineated, and molecular testing serves as a useful adjunct diagnostic tool in cases with unusual morphology and/or clinical presentation. We herein present a case of an epithelioid haemangioma of deep soft tissue with an unusual intravascular growth pattern, harbouring a novel SETD1B-FOSB gene fusion. A 33-year-old female presented with a painful deep soft tissue mass on the left posterior chest wall of 3 years duration. The initial clinical impression was a possible vascular malformation. Computed tomography (CT) angiogram showed a solitary, non-enhancing, 1.7 cm nodular lesion between the left 8th and 9th ribs underlying the posterior latissimus dorsi. No feeding vessel was identified. As the patient experienced persistent, severe pain that did not respond to conventional analgesia and radiofrequency ablation, hookwire-guided excision of the nodule was performed. Histological evaluation of the excised specimen showed skeletal muscle and fibroadipose tissue involved by an epithelioid tumour with a predominantly intravascular growth pattern, filling the lumina of medium sized blood vessels (Fig. 1A–C). The tumour comprised solid aggregates of relatively uniform epithelioid cells with round, centrally placed nuclei and ample eosinophilic cytoplasm (Fig. 1D). Vascular lumina were inconspicuous. No accompanying inflammatory infiltrate or myxohyaline stroma was seen. There was no high grade nuclear atypia, mitotic activity or necrosis. On immunohistochemistry, the epithelioid tumour cells showed positive expression of endothelial markers ERG and CD31 (Fig. 1E,F), and were negative for SMA, Cam5.2, AE1/3, desmin, TFE3 and CAMTA1. The overall findings were most in keeping with an epithelioid haemangioma with a predominant intravascular growth pattern. Anchored multiplex polymerase chain reaction (PCR) analysis (FusionPlex custom assay; Archer, USA) detected a novel SETD1B (exon 4)-FOSB (exon 2) gene fusion (Fig. 2), which was subsequently confirmed by reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing. There was no clinical or radiological evidence of recurrent disease at one year follow-up.Fig. 2A gene fusion between SETD1B (exon 4) and FOSB (exon 2) was detected by anchored multiplex PCR analysis (Archer FusionPlex Solid Tumour Assay, top panel). RT-PCR and Sanger sequencing shows the junction sequence between SETD1B exon 4 and FOSB exon 2 (bottom panel).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Epithelioid haemangioma (EH) is an uncommon, benign vascular neoplasm that mainly affects adults aged 20–50 years with no gender predominance.1Fletcher C.D.M. Bridge J.A. Hogendoorn P.C.W. et al.World Health Organization Classification of Tumours of Soft Tissue and Bone.4th ed. IARC Press, Lyon2013Google Scholar Initially described as having a predilection for the skin and subcutis of the head and neck, later studies have reported various anatomical locations including the deep soft tissue, bone, lymph nodes, viscera, eyes and penis.2Fetsch J.F. Sesterhenn I.A. Miettinen M. et al.Epithelioid hemangioma of the penis: a clinicopathologic and immunohistochemical analysis of 19 cases, with special reference to exuberant examples often confused with epithelioid hemangioendothelioma and epithelioid angiosarcoma.Am J Surg Pathol. 2004; 28: 523-533Crossref PubMed Scopus (66) Google Scholar Typically, it has a lobulated growth pattern, well-circumscribed or pushing borders, and well-formed vascular channels lined by prominent epithelioid endothelial cells. There is usually abundant accompanying stromal chronic inflammation, with a brisk eosinophilic infiltrate characteristic of most lesions.1Fletcher C.D.M. Bridge J.A. Hogendoorn P.C.W. et al.World Health Organization Classification of Tumours of Soft Tissue and Bone.4th ed. IARC Press, Lyon2013Google Scholar However, EH also displays a diverse range of histological appearances, which if under- recognised may pose diagnostic pitfalls. We report this unusual case of EH arising in the deep soft tissue of the chest wall, as it shows several features not typically seen in its cutaneous counterpart in the head and neck region. In particular, the intravascular growth pattern, solid architecture, minimal vasoformative features and absence of accompanying inflammatory infiltrate are emphasised. Although EH with focal solid growth is not uncommon, a predominantly solid growth pattern with minimal peripheral maturation, as seen in our case, is rare.2Fetsch J.F. Sesterhenn I.A. Miettinen M. et al.Epithelioid hemangioma of the penis: a clinicopathologic and immunohistochemical analysis of 19 cases, with special reference to exuberant examples often confused with epithelioid hemangioendothelioma and epithelioid angiosarcoma.Am J Surg Pathol. 2004; 28: 523-533Crossref PubMed Scopus (66) Google Scholar In addition to the lack of overt vasoformation, the loco-regionally confined intravascular growth pattern is also uncommonly described, particularly in non-cutaneous EH.3Luzar B. Ieremia E. Antonescu C.R. et al.Cutaneous intravascular epithelioid hemangioma. A clinicopathological and molecular study of 21 cases.Mod Pathol. 2020; 33: 1527-1536Crossref PubMed Scopus (6) Google Scholar An eosinophilic stromal infiltrate is a classic feature of EH, as reflected in the original description of this entity, angiolymphoid hyperplasia with eosinphilia (ALHE). However, it has since been recognised that the eosinophilic stromal infiltrate is only occasionally seen in deep seated soft tissue or bone EH,4Errani C. Zhang L. Panicek D.M. et al.Epithelioid hemangioma of bone and soft tissue: a reappraisal of a controversial entity.Clin Orthop Relat Res. 2012; 470: 1498-1506Crossref PubMed Scopus (57) Google Scholar as illustrated in this case. For cases of EH with unusual histological features, ancillary molecular tests may be helpful in providing a higher degree of diagnostic confidence and excluding more aggressive epithelioid vascular neoplasms such as epithelioid haemangioendothelioma and epithelioid angiosarcoma. In recent years, several gene rearrangements involving FOSB and FOS genes have been described in EH, and are summarised in a recent review.5Papke Jr., D.J. Hornick J.L. What is new in endothelial neoplasia?.Virchows Arch. 2020; 476: 17-28Crossref PubMed Scopus (16) Google Scholar ZFP36-FOSB fusion has been described in a subset of EH with atypical features,6Antonescu C.R. Chen H.-W. Zhang L. et al.ZFP36-FOSB fusion defines a subset of epithelioid hemangioma with atypical features.Genes Chromosomes Cancer. 2014; 53: 951-959Crossref PubMed Scopus (90) Google Scholar whilst FOS-LMNA fusion has been observed in a third of EHs across different anatomical locations and histological variants and VIM-FOS fusion was identified in two cases of intraosseous cellular EH.7Huang S.-C. Zhang L. Sung Y.-S. et al.Frequent FOS gene rearrangements in epithelioid hemangioma: a molecular study of 58 cases with morphologic reappraisal.Am J Surg Pathol. 2015; 39: 1313-1321Crossref PubMed Scopus (92) Google Scholar Cases of EH showing FOSB or FOS gene rearrangements have been reported to be enriched in morphological variants displaying solid growth, atypical features and less conspicuous eosinophilic infiltrate.6Antonescu C.R. Chen H.-W. Zhang L. et al.ZFP36-FOSB fusion defines a subset of epithelioid hemangioma with atypical features.Genes Chromosomes Cancer. 2014; 53: 951-959Crossref PubMed Scopus (90) Google Scholar,7Huang S.-C. Zhang L. Sung Y.-S. et al.Frequent FOS gene rearrangements in epithelioid hemangioma: a molecular study of 58 cases with morphologic reappraisal.Am J Surg Pathol. 2015; 39: 1313-1321Crossref PubMed Scopus (92) Google Scholar Interestingly, our case which similarly displayed some of these unusual histological traits also harboured a genetic rearrangement in the FOSB gene, with a novel fusion partner SETD1B. Of note, FOSB gene rearrangements were not detected in a recent case series of cutaneous intravascular EH, suggesting different genetic underpinnings of cutaneous versus non-cutaneous intravascular EHs.3Luzar B. Ieremia E. Antonescu C.R. et al.Cutaneous intravascular epithelioid hemangioma. A clinicopathological and molecular study of 21 cases.Mod Pathol. 2020; 33: 1527-1536Crossref PubMed Scopus (6) Google Scholar The FOS gene family consists of four members: FOS (chromosome 14q24.3), FOSB (chromosome 19q13.32), FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerise with proteins of the JUN family, constituting the major components of the transcription factor complex AP-1 (Activating Protein-1). The AP-1 transcription factor binds to TPA-responsive elements (TREs; 5′-TGAC/GTCA-3′) of the promoter and enhancer regions of target genes, and is critical for accurate regulation of numerous genes implicated in cell proliferation, differentiation, apoptosis, angiogenesis, oncogenic transformation and tumour progression.8Durchdewald M. Angel P. Hess J. The transcription factor Fos: a Janus-type regulator in health and disease.Histol Histopathol. 2009; 24: 1451-1461PubMed Google Scholar Although the functional roles of the FOSB and FOS gene rearrangements in EH have not been well-characterised, there is evidence of increased expression of FOSB and FOS mRNA expression in cases of FOSB- and FOS-fusion positive EH, respectively, compared to the other types of vascular neoplasms.6Antonescu C.R. Chen H.-W. Zhang L. et al.ZFP36-FOSB fusion defines a subset of epithelioid hemangioma with atypical features.Genes Chromosomes Cancer. 2014; 53: 951-959Crossref PubMed Scopus (90) Google Scholar,7Huang S.-C. Zhang L. Sung Y.-S. et al.Frequent FOS gene rearrangements in epithelioid hemangioma: a molecular study of 58 cases with morphologic reappraisal.Am J Surg Pathol. 2015; 39: 1313-1321Crossref PubMed Scopus (92) Google Scholar In the FOSB-fusion EH index cases, there was also an increase in the mRNA expression of IL8,7Huang S.-C. Zhang L. Sung Y.-S. et al.Frequent FOS gene rearrangements in epithelioid hemangioma: a molecular study of 58 cases with morphologic reappraisal.Am J Surg Pathol. 2015; 39: 1313-1321Crossref PubMed Scopus (92) Google Scholar a gene that encodes a FOSB regulated protein which plays a role in stress induced tumour growth and microvessel density.9Shahzad M.M.K. Arevalo J.M. Armaiz-Pena G.N. et al.Stress effects on FosB- and interleukin-8 (IL8)-driven ovarian cancer growth and metastasis.J Biol Chem. 2010; 285: 35462-35470Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Of note, recurrent FOSB fusions (SERPINE1-FOSB, WWTR-FOSB and ACTB-FOSB fusions) have also been described in pseudomyogenic haemangioendothelioma,10Panagopoulos I. Lobmaier I. Gorunova L. et al.Fusion of the genes WWTR1 and FOSB in pseudomyogenic hemangioendothelioma.Cancer Genomics Proteomics. 2019; 16: 293-298Crossref PubMed Scopus (22) Google Scholar another uncommon vascular neoplasm with borderline malignant potential. SETD1B (SET domain containing 1B), also known as KMT2G, is a member of the KMT2 family of histone H3K4 methyltransferases that mediates genome accessibility and transcription. The KMT2 family dependent epigenetic regulation is implicated in several biological processes, including tumour development and progression.11Rao R.C. Dou Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases.Nat Rev Cancer. 2015; 15: 334-346Crossref PubMed Scopus (284) Google Scholar Whilst SETD1B/KMT2G has not been previously implicated in mesenchymal neoplasms, gene fusions involving another member of the KMT2 family (KMT2A/MLL) have been recently described in aggressive sarcomas in young adults, suggesting a broader role for KMT2 family of histone methyltransferases in the pathogenesis of mesenchymal tumour.12Yoshida A. Arai Y. Tanzawa Y. et al.KMT2A (MLL) fusions in aggressive sarcomas in young adults.Histopathology. 2019; 75: 508-516Crossref PubMed Scopus (13) Google Scholar In summary, we have identified a novel SETD1B-FOSB gene fusion in a case of intravascular EH of deep soft tissue with uncommon histological features. This supports the association of certain unusual morphological features of EH with recurrent genetic rearrangements in the FOS gene family, hinting at a distinct subgroup defined by FOS gene family alterations within this heterogenous entity. We thank Professor Brian Rubin for his assistance with this case.