# Identification of a GATA6::FOXO1 fusion in a case of cutaneous epithelioid angiomatous nodule: further evidence supporting its classification as an epithelioid haemangioma variant?

Irena Antonia Ungureanu, Nathalene Truffaut, Rihab Azmani, Francois Le Loarer, Raul Perret

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Irena Antonia Ungureanu, Nathalene Truffaut, Rihab Azmani, Francois Le Loarer, Raul Perret. Identification of a GATA6::FOXO1 fusion in a case of cutaneous epithelioid angiomatous nodule: further evidence supporting its classification as an epithelioid haemangioma variant?. Histopathology, 2025, 10.1111/his.15439. hal-04988699

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Submitted on 12 Mar 2025

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Correspondence

Identification of a GATA6::FOXO1 fusion
in a case of cutaneous epithelioid
angiomatous nodule: further evidence
supporting its classification as an
epithelioid haemangioma variant?

DOI: 10.1111/his.15439

© 2025 John Wiley & Sons Ltd.

Sir. Cutaneous epithelioid angiomatous nodule (CEAN) is a rare, benign vascular lesion, typically presenting as single or multiple superficial cutaneous nodules arising on the trunk and extremities in young adults.¹ Morphologically, CEAN comprises a well-circumscribed dermal nodule made of sheets of epithelioid cells with round vesicular nuclei and abundant eosinophilic cytoplasm with frequent vacuolisation (primitive lumen). True vascular formation is generally a focal finding. The morphological features of CEAN closely resemble those seen in epithelioid haemangioma (EH), with the main proposed distinctions being a greater abundance of vascular channels, more pronounced inflammation and a deeper location in EH.

The aetiopathogenesis and molecular underpin-
nings of CEAN remain poorly explored, and it has
been debated whether it represents a benign reactive
lesion or a variant of EH. In this report, we present a
case of CEAN harbouring a GATA6::FOXO1 gene
fusion, a molecular alteration that has been exclu-
sively reported in EH.²⁻⁴

A 60-year-old female presented with a solitary 5-
mm cutaneous lesion on her abdomen, which was
excised. Microscopic analysis revealed a well-circum-
scribed and nodular vascular proliferation centred in
the superficial dermis (Figure 1A). Intralesional vas-
cular channels were focally present and heteroge-
neously distributed (Figure 1B). The tumour consisted
of sheets of epithelioid cells with monomorphic round
to oval nuclei, centred by a small nucleolus
(Figure 1C,D). The cytoplasm was abundant and
eosinophilic, with occasional vacuolisation. Tumour
necrosis and mitoses were absent. Additional findings
included a minimal lymphocytic inflammatory

infiltrate. Immunohistochemistry showed strong posi-
tivity for CD34, CD31 and ERG.

Based on the histopathological features, a diagnosis
of CEAN was rendered. As the molecular landscape of
CEAN is unknown, to gain further insight a tran-
scriptomic characterisation of the lesion was per-
formed. Whole-RNA sequencing (TruSeq, Illumina,
San Diego, CA, USA) revealed a GATA6::FOXO1
(Figure 1E). As this was a recent case, no significant
follow-up data was available.

Benign epithelioid vascular lesions are rare, cur-
rently encompassing EH and CEAN. Epithelioid hae-
mangioma presents as single or multiple nodules
arising in the soft tissue, skin or bone. While EH
shows no metastatic potential, it may recur locally
and exhibit destructive growth. Histologically, EH is
characterised by a lobulated growth pattern, variable
inflammation, well-formed vascular channels lined by
plump epithelioid cells and solid areas. The proportion
of well-formed vascular channels and solid areas var-
ies from case to case.

Several histological subtypes of EH have been
described, including conventional, cellular and mixed
spindle and epithelioid variants. Furthermore, a form
known as angiolymphoid hyperplasia with eosino-
philia (ALHE) is also considered to fall within the
spectrum of EH. Notably, EH represents a molecularly
heterogeneous group of tumours, with a variable pro-
portion of cases harbouring gene fusions/
rearrangements involving FOS or FOSB. The fusions/
rearrangements appear to be more frequent in cellu-
lar variants and in tumours arising in the deep soft
tissues, penis and bone. In contrast, head and neck
EH and ALHE frequently lack FOS rearrangements,
suggesting the presence of alternative pathogenetic
events.⁵

Recently, the molecular landscape of EH has been
widened with the discovery of novel GATA6::FOXO1
fusions in a subset of cases. The tumours arose in
various locations, including the head and neck, trunk
and extremities, with some cutaneous examples
centred in the superficial dermis. Compared to EH
with FOS/FOSB fusions/rearrangements, GATA6::
FOKO1 fused tumours exhibited a more solid growth
pattern, a paucity of blister cells and some degree of
nuclear atypia, including conspicuous nucleoli and
mild to moderate pleomorphism. All tumours showed
a benign behaviour.²⁻⁴

The identification of a GATA6::FOXO1 fusion in a
case of CEAN suggests that at least a subset of these

<footnote>**Abbreviations:** CEAN, Cutaneous epithelioid angiomatous nodule; EH, Epithelioid haemangioma; ALHE, angiolymphoid hyperplasia with eosinophilia.</footnote>
<figure><img src="image_3.png" /><figcaption>**Figure 1.** Histopathological and molecular findings of Cutaneous Epithelioid Angiomatoid Nodule with a GATA6::FOXO1 fusion. A. Panoramic view showing a cutaneous nodular lesion centred in the superficial dermis. B. The lesion showed a predominantly solid architecture with heterogeneously distributed vascular channels. C,D. The tumour was composed of solid sheets of epithelioid cells with frequently vacuolated eosinophilic cytoplasm and round nuclei with conspicuous nucleoli. Inset shows ERG immunohistochemistry. E. Schematic representation of the GATA6::FOXO1 gene fusion detected in the tumour.</figcaption></figure>

tumours share a molecular signature with EH. Furthermore, CEAN shows substantial clinical and morphological overlap with the subset of EH with GATA6::FOXO1 fusions, including no clear gender predilection, a similar median age onset (young adults in their 30s), comparable anatomical distribution, superficial location, benign behaviour and a

predominantly solid architecture with limited vasofor-mation. Altogether, these observations support the notion that CEAN is a true neoplasm, which falls in the spectrum of EH. However, additional case series of CEAN with molecular characterisation are needed to determine its place in the classification of epithelioid vascular tumours.
In conclusion, we report a case of a CEAN harbouring a GATA6::FOXO1 gene fusion. Whether CEAN should be considered an independent entity or a variant of EH needs to be addressed in future consensus. We believe the latter to be the most adequate interpretation, as it will prevent unnecessary fragmentation of increasingly complex tumour classifications.

## Acknowledgements

None declared.

## Conflicts of interest

None reported.

## Data availability statement

The data sets used and/or analysed during the current study are available from the corresponding authors on reasonable request.

Irena Antonia Ungureanu¹ ID

Nathalene Truffaut²

Rahab Azmani³

François Le Loarer²,⁴,⁵ ID

Raul Perret²,⁵ ID

¹Pathology Department, Paris-Saclay University, Versailles SQY University (UVSQ), EA4340-BECCOH, Ambroise-Paré Hospital, Boulogne-Billancourt, ²Biopathology Department, ³Bioinformatics, Data and Digital Health Department, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, ⁴University of Bordeaux, Talence and ⁵INSERM U1218, ACTION, Institut Bergonié, Bordeaux, France

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