
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)13763-2
10.1016/j.heliyon.2024.e37732
e37732
Case Report
Diffuse skin erythematous plaque as a manifestation of epithelioid hemangioendothelioma: A case report
Pan Ruoxin a1
Wang Chuang b1
Gu Duoduo a
Meng Xiaoqi a
Liu Tingwei a
Zhong Hui c
Gong Qixing gongqixing@hotmail.com
d⁎⁎
Xu Yang yangxu@njmu.edu.cn
a⁎
a Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
b Department of Dermatology, Taizhou Hospital of Traditional Chinese Medicine, Taizhou, 225300, China
c State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
d Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
⁎ Corresponding author. yangxu@njmu.edu.cn
⁎⁎ Corresponding author. gongqixing@hotmail.com
1 These authors contributed equally to this work.

10 9 2024
30 9 2024
10 9 2024
10 18 e377324 6 2024
5 9 2024
9 9 2024
© 2024 The Authors. Published by Elsevier Ltd.
2024

https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Epithelioid hemangioma (EHE) is a rarely malignant tumor originating from the vascular endothelium. Morphological manifestations and immunohistochemical staining results are key to diagnosing EHE. Herein, we present a case of cutaneous involment in a recurrence of EHE. A 75-year-old woman presented with a month-long history of persistent erythematous plaque and pain in the left shoulder. Skin biopsy specimen revealed epithelioid tumor cells containing abundant eosinophilic cytoplasm. Immunohistochemical staining confirmed a recurrence of EHE involving the skin. Subsequently, recombinant human endostatin was administered. At the 10-day follow-up, the cutaneous plaque had improved, and the pain had resolved. When presenting as a local painful erythematous plaque, the possibility of skin involvement in a malignant tumor should be considered. Early diagnosis and early systemic therapy have an important impact on the overall survival of patients with EHE.

Highlights

• Epithelioid hemangioendothelioma is a malignant tumor of the vascular endothelium. Morphological manifestations and immunohistochemical staining results are the key to the diagnosis of EHE.

• We noted a recurrence of soft tissue EHE involving the skin, manifesting as carcinoma erysipeloides. The possibility of skin involvement in malignant tumor should be considered when patients present with a locally painful erythematous plaque.

• Epithelioid hemangioendothelioma with cutaneous involvement often has a poor prognosis and systemic therapy should be initiated at the earliest.

Keywords

Epithelioid hemangioendothelioma
Skin neoplasms
WWTR1-CAMTA1
Case report
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pmc1 Introduction

Epithelioid hemangioendothelioma (EHE) is a malignant tumor originating from the vascular endothelium and commonly occurs in the soft tissues, skin, lungs, liver, and bones. Herein, we present a case of cutaneous involment in a recurrence of EHE, manifesting as carcinoma erysipeloides and characterized by painful indurated erythematous plaques. These manifestations may be misdiagnosed as erysipelae or cellulitis.

2 Case presentation

A 75-year-old woman presented to the Dermatology department in September 2023 with a month-long history of persistent erythematous plaque and pain in the left shoulder. She was treated with oral cephalosporins for 1 day, but her symptoms did not improve. Physical examination revealed diffusely indurated erythematous plaques with clustered pustules and crusts localized on the left shoulder and back. The left upper limb was absent (Fig. 1A). Five months ago, the patient presented to the Department of Orthopedics with complaints of left upper limb pain and numbness for over 4 months, accompanied by limited mobility. Computed tomography angiography revealed an irregular soft tissue mass in the left axilla adjacent to the axillary and brachial arteries (Fig. 2). The patient subsequently underwent shoulder disarticulation and upper limb vessel ligation. Pathology results indicated that the tumor measured 6 × 2.2 × 2 cm, and was adjacent to the superior and inferior resection margins, while the anterior, posterior, left, and right margins were free of tumor involvement. Immunohistochemical analysis confirmed the diagnosis of EHE. She had been administered imatinib mesylate 1 month prior because of a chest wall soft tissue mass with nodules on a computed tomography scan, which was considered a metastasis.Fig. 1 (A)Physical examination showing a diffuse indurated erythematous plaque (measuring 200 × 200 mm) with clustered pustules and crusts localized to the left shoulder and back. (B)Follow-up after 10 days of treatment, showing a noticeable reduction in induration and erythema, along with a decrease in the size of the plaque and the presence of more pustules and crusts.

Fig. 1

Fig. 2 Computed tomography angiography showing an irregular soft-tissue mass in the left axilla (green lines).

Fig. 2

Pathological examination of the skin biopsy specimen revealed epithelioid tumor cells containing abundant eosinophilic cytoplasm arranged in a nest. Moreover, active tumor cell division with a small focus on necrosis was observed, suggesting cutaneous involvement of carcinoma (Fig. 3). Immunohistochemical staining revealed positive expression of CD31 (++)(Fig. 4A), CD34 (partial+)(Fig. 4B), ERG (+)(Fig. 4C), and Ki67 (50 %+)(Fig. 4D) and negative expression of CK7, GATA3, ER, PR, CK5/6, EMA, TRPS1, and TFE3. The results of fluorescence in situ hybridization (FISH) in the present case also showed a positive WWTR1-CAMTA1 fusion gene, confirming cutaneous involvement in EHE (Fig. 5).Fig. 3 Neoplastic cells showing active nuclear division, accompanied by focal necrosis. Magnification × 200.

Fig. 3

Fig. 4 Immunohistochemical staining showing positive results for CD31(A), CD34(B), ERG (C), and Ki67(D). Magnification × 200.

Fig. 4

Fig. 5 Fluorescence in situ hybridization is characteristically positive for WWTR1-CAMTA1 (white arrow).

Fig. 5

A final diagnosis of cutaneous involvement in EHE was made, but the patient refused further systemic evaluation, and only recombinant human endostatin (Rh-endostatin, Simcere, China) was administered. At the 10-day follow-up, the cutaneous plaque had improved, and the pain had resolved (Fig. 1B). However, at a 1-month follow-up, she was found to have died of multiple organ dysfunction at a local hospital.

3 Discussion

In 1982, Weiss and Enzinger first described epithelioid hemangioendothelioma, defining it as a borderline vascular tumor with a clinical behavior between benign hemangioma and malignant angiosarcoma [1]. According to the World Health Organization classification of soft tissue and bone tumors published in 2020, EHE is formally classified as a malignant vascular tumor.

The diagnosis of EHE is primarily based on its characteristic microscopic appearance and immunohistochemical staining. The classic EHE is characterized by the following features: The epithelioid cells are dispersed within a myxochondroid or hyalinized stroma, organized in nests or strands. Usually, tumor cells exhibit an eosinophilic cytoplasm on hematoxylin and eosin (H&E) staining, within which large vacuoles can be observed. Aggressive EHE is characterized by high nuclear grade, increased mitotic activity, the presence of a solid growth pattern, and tumor necrosis, all of which indicate a higher level of biological aggressiveness [2]. Immunohistochemical staining revealed the expression of common markers of vascular origin, such as CD31, CD34, ERG, and FLI-1. In the present case, H&E staining results showed active nuclear division accompanied by focal necrosis, with immunohistochemistry revealing a high Ki-67 %, indicating a more aggressive tumor.

EHE can be categorized based on the presence of different fusion genes. EHE with WWTR1-CAMTA1 and YAP1/TFE3 fusion genes constituted approximately 90 % and 10 % of the cases, respectively [3]. In addition, their pathological manifestations vary. WWTR1-CAMTA1 EHE was characterized by epithelioid cells arranged in cords and nests, whereas YAP1-TFE3 EHE was characterized by solid nests separated by fibrous septa [4]. WWTR1 (TAZ) and YAP1 are transcriptional effectors of the Hippo signaling pathway. The interaction of WWTR1 or YAP1 with TEAD transcription factors leads to the dysregulation of the Hippo pathway [4,5].

Additionally, CAMTA1 and TFE3 can confer chromatin-remodeling properties [6]. The combined effects of the two fusion genes drive oncogenesis. Patients with the YAP1/TFE3 fusion gene tended to be younger and have longer survival times than those with the WWTR1-CAMTA1 fusion gene. However, the identification of fusion genes has no prognostic or predictive value, nor can it offer treatment stratification and medical guidance [7]. To clarify the diagnosis, FISH testing can be utilized to confirm EHE when the diagnosis is uncertain.

In most cases, skin metastasis of EHE is found near the primary site and may develop within months or years after the primary tumor diagnosis or simultaneously. Only four cases of cutaneous metastasis of EHE have been reported in the literature, as listed in Table 1, most of which presented as violaceous nodules. In this particular case, however, the cutaneous involvement represents local tumor recurrence rather than metastasis. Given the proximity of the tumor to the superior and inferior margins, this resection would be classified as an R1 resection rather than an R0 resection. Consequently, the patient experienced local tumor recurrence, with extension into the overlying skin. This manifestation was observed as carcinoma erysipeloides, characterized by a painful erythematous plaque. Carcinoma erysipeloides is a clinical manifestation of skin metastasis, which can be seen in breast cancer and lung adenocarcinoma [8,9]. As illustrated in this case, the patient presented with a local painful erythematous plaque, the possibility of skin involvement in malignant tumor should be considered. Dermatologists should inquire about medical history and promptly perform a skin biopsy for further evaluation.Table 1 Four cases of cutaneous metastasis of epithelioid hemangioendothelioma in the literature.

Table 1Case	Author	Age, years	Sex	Primary sites	Location of skin lesions	Cutaneous presentation	Immunohistochemistry	Follow-up	
1	Al-Shraim et al. [15]	51	Male	Lung	Anterior abdominal wall	Subcutaneous nodule	CD31, CD34, vimentin, CEA	More cutaneous nodules developed on his trunk.	
2	Cooper et al. [16]	58	Male	Liver	Left proximal thigh and the right upper lip	Violaceous lesion	CD31, CD34	Died of respiratory failure 3 months after pulmonary metastasis.	
3	Tyring et al. [17]	21	Male	Bone	Right anterior thigh	Firm, slightly violaceous nodules	FVIII	No recurrence 10 months after surgery.	
4	Ro et al. [18]	76	Male	Lung	Right lower leg	Erythematous umbilicated nodule	CD31, CD34, FVIII, S100 protein	No recurrence 4 months after surgery.	

Survival analysis showed that the 1-, 3-, and 5-year survival rates of patients with EHE were 70.8 %, 61.2 %, and 55.6 %, respectively [10]. Shorter overall survival was associated with multifocal tumors, metastasis, lymph node involvement, and lung primary tumors [11]. According to the European Society for ESMO consensus, active surveillance is recommended for asymptomatic patients with metastatic disease who cannot undergo complete resection. Patients with metastatic lesions, disease progression, or organ dysfunction should receive systemic therapy as soon as possible [7]. Owing to the low incidence of EHE, little is known about proper therapy. In addition, diffuse infiltrative lesion made excision impossible. Rh-endostatin has been reported to be effective for advanced non-small cell lung cancer, advanced esophageal squamous cell carcinoma, advanced or recurrent mucosal melanoma, and other malignant tumors, owing to its inhibition of angiogenesis [[12], [13], [14]]. Our patient refused further systemic evaluation, and only rh-endostatin was administered as the major regimen, which did not obviously improve survival. The survival duration was relatively poor, ranging from only two months after the development of recurrence to death. Currently, three clinical trials are underway to evaluate the effects of eribulin, trametinib, and IK-930 (TEAD inhibitors) on EHE (ClinicalTrials.gov identifiers: NCT03331250, NCT05228015, and NCT03148275).

4 Conclusion

We report cutaneous involment in a recurrence of EHE. When presenting as a local painful erythematous plaque, the possibility of skin involvement in malignant tumor should be considered. Morphological manifestations and immunohistochemical staining results are key to diagnosing EHE. EHE with skin involvement often indicates a poor prognosis, and systemic therapy should be initiated as early as possible in this situation.

Ethical approval statement

Review and approval by an ethics committee was not needed for this study because it is a case report that involves the retrospective analysis of de-identified patient data, and no experimental interventions or deviations from standard clinical practice were performed.

Consent for publication

Written informed consent was obtained from the patient. And the patient consented to the publishing of all images, clinical data, and other data included in the manuscript. The patient was provided with comprehensive information about the purpose and consented to the publication.

Funding

None.

Data availability statement

No data was used for the research described in the article.

CRediT authorship contribution statement

Ruoxin Pan: Writing – original draft, Investigation, Data curation. Chuang Wang: Resources, Investigation, Data curation. Duoduo Gu: Investigation. Xiaoqi Meng: Investigation. Tingwei Liu: Visualization. Hui Zhong: Supervision. Qixing Gong: Validation. Yang Xu: Writing – review & editing, Validation.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We would like to thank Editage for the English language editing.
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