Epithelioid hemangioendotheliomas (EHE) are rare neoplasms that arise from epithelial cells lining the blood vessels and have clinical presentations that vary in aggressiveness ^,, . EHE of the skin typically originates from medium to large veins of the superficial and deep soft tissue . These tumors can appear anywhere within the body with predilections for the lungs, liver, and bone ^, . EHE of the lungs and liver are more commonly reported in women than men. EHE elsewhere in the body has been found to impact men and women equally and without an age predilection, though most present within the third, fourth, and fifth decades of life ^,, . EHE can present in childhood, though it is extremely rare .

EHEs typically present with a painful, poorly circumscribed lesion demonstrating a red or blue pigment, sometimes associated with edema and thrombophlebitis ^, . Systemic symptoms of EHE may include nausea, fever, difficulty walking, and weight loss . Biopsy and imaging techniques aid in diagnosis, while full excision of this uncommon lesion provides definitive diagnosis . Genetically, 90 % of EHEs are found to have a special WWTR1-CAMTA1 fusion that defines the lesion and is not found in similar tumors ^, . Histological atypia is associated with a more clinically aggressive form of the tumor . Immunohistochemical staining for EHE typically stains positive for Factor VIII, Ulex europaeus , CD31, CD34, and ERG, with variability in keratin staining ^, . CD31 and CD34 are commonly used immunohistochemical markers that can be expressed in different vascular tumors. Thus, it is critical to assess both immunohistochemical markers and histopathology for differentiation of EHE from other vascular tumors ^,, .

Although EHEs tend to be of low-grade malignancy, they can have an aggressive course. EHE is an uncommon tumor of the lower extremity and requires a high index of suspicion and comprehensive diagnostic workup when considered. We describe a case report of a vascular lesion located on the plantar foot of a 27-year-old female, where EHE was strongly suspected on biopsy. Fortunately, full excision revealed benign endothelial hyperplasia without malignancy.

A 27-year-old female with BMI 35 with no other comorbidities presented with a persistent painful lump on her left plantar foot after wearing a pair of poorly fitting shoes a few months prior. She underwent an ultrasound, which was suggestive of a ganglion, epidermal inclusion cyst, vs hematoma, which prompted fine needle aspiration (FNA). 2 mL of brown-colored fluid was collected and stained with H&E and Papanicolaou. The pathology report was consistent with a hematoma with normal RBCs and no malignant cells. FNA temporarily relieved the patient’s symptoms. Approximately four months later, the patient presented with a recurring, raised, painful lump ( Fig. 1 ).

Pre-operative gross image of the suspected epithelioid hemangioendothelioma.

In the setting of increased mass size and patient reported symptoms, a punch biopsy of the plantar lump was performed. 0.5 × 0.4 × 0.2 cm aggregate of pale-tan tissue fragments were fixed in formalin, embedded in paraffin wax on one cassette, and underwent microscopic evaluation. Pathology revealed that a detached vascular tumor with features of hemangioendothelioma with suspected low-grade malignancy was present. Features included inter-anastomosing channels of endothelial cells with a sclerotic-like stroma. Special stains showed endothelial cells were positive for vascular marker CD34, and pan-keratin negative, suggesting a low-grade malignancy may be present. Due to the biopsy revealing a potentially malignant mass, the patient then underwent a full-body positron emission tomography-computed tomography (PET-CT) scan. PET-CT revealed no suspicious fluorodeoxyglucose (FDG) avid lesions, but a hypermetabolic left inguinal lymph node was present.

The patient underwent a complete, wide-margin surgical excision with a surgical oncologist at a local University Cancer Research Medical Center. The final surgical pathology analysis noted a 0.6 × 0.3 × 0.2 cm brown-black-colored ovoid lesion with intravascular papillary endothelial hyperplasia present. Sections showed a dilated vessel centered in the superficial subcutaneous tissue with associated intravascular proliferation of reactive endothelial cells, forming multiple papillary structures lined by a singular layer of plump endothelial cells. There was no necrosis, areas of infiltrative growth, mitotic figures, nor marked cytological atypia, indicating no malignancy was identified. No surgical or post-operative complications were reported, and the patient resumed ambulation with full weight bearing after approximately two weeks. No signs of recurrence have been reported after 6 months of follow-up.

The earliest reported EHE was reported in 1979 by Rosai et al. as a generalized term known as “histiocytoid hemangiomas.” It was not until Weiss and Enzinger conducted a retrospective study of 41 cases in 1982 that they coined the term used today as EHE. The researchers highlighted that epithelioid endothelial cells may appear in other benign vascular tumors, and their aggressiveness should be evaluated to determine EHE diagnosis .

While EHEs primarily appear in the lung, liver, and bone, they can also appear in the lower extremities. The retrospective study by Weiss and Enzinger noted that the most common location was in the extremities with fourteen of the forty-one cases (34 %) found in the lower extremity, with the majority originating from veins. Six of the fourteen (43 %) lower extremity EHEs were found in the knee, lower leg, and foot. Namely, Weiss and Enzinger report that of their few cases, nearly 50 % of EHEs in the lower extremity were located at or distal to the knee joint .

To date, there are few published cases and no reviews of EHEs located in the foot and ankle. A literature review was conducted to identify cases of EHE reported in the foot and ankle. Keywords such as “epithelioid hemangioendothelioma, foot, ankle, vascular tumor” will be integrated in an advanced search on NIH, PubMed, EBSCO host and Google Scholar. Case reports of EHE located from the ankle to the distal phalanges were included. Retrospective reports and EHEs located proximal to the talocrural joint will be excluded. Our literature review highlights that there are seven case reports describing EHE located in the foot and ankle ( Table 2 ). Although these lesions are rarely reported in the foot and ankle, they still occur and need to be promptly addressed. Lower extremity lesions present differently depending on location. The lesion may present as a slow growing, pigmented, painful nodular mass or a spontaneously appearing, non-healing open lesion ^,,, . However, if the lesion is localized to the bone, the patient may complain of localized pain in the area without clinical appearance ^, .

Furthermore, Bakotic et al. describes a case in 1999 of a 50-year-old man with a spontaneous fracture of the left fourth toe and ultimately underwent amputation to the fourth toe and metatarsal head after subtotal lytic destruction and resorption of the bone . In addition, Forschner et al. described an 11-year-old girl with an ulcerative painful cutaneous lesion located on the instep of her right foot. Although wide excision was performed, she ultimately experienced metastasis and required polychemotherapy to address an inaccessible lesion . Moreover, Bisbinas et al. reported a case in 2006 of a 41-year-old male with chronic left ankle pain who was difficult to diagnose. He was initially treated with fixation and received antibiotics for deep tissue infection. When the patient presented four months later with unresolved symptoms, the patient’s second biopsy revealed aggressive metastatic EHE. The patient denied below-the-knee amputation and instead underwent intervention involving fusion of joints and curettage of lesions . Additionally, Carranza-Romero et al. highlighted the youngest case of EHE of the sole of the left foot in a 6-year-old male who underwent wide resection of the lesion without adjunctive therapy . Also, Go et al. described two case reports: one 35-year-old female and one 44-year-old male both presented with localized pain in the foot and ankle, respectively. The female patient underwent excision with packing of the lesion cavity with methyl methacrylate and post-operative radiation to the posterior aspect of her left os calcis. Although successful for four years, the patient had recurrent lesions in the distal fibula and distal phalanx of the left great toe, which were treated with radiation therapy . Go et al. and Forschner et al. were the only case reports with recurrence. In the case of the male patient, the presentation of an inoperative progressed lesion was confirmed and was subsequently and successfully treated with radiotherapy .

The standard of care for EHE is surgical excision with clear margins when possible. Although some cases report that wide excision of lesions is sufficient, adjunct therapy may be necessary to halt progression. Additionally, radiation may be an important adjunct therapy to prevent recurrence . Radiotherapy may also be used in cases where the lesion is inaccessible or too destructive for limb salvage . In the case of distal metastasis to regional lymph nodes or other tissue, chemotherapy is usually considered . In some extreme cases where a course of surgical resection and adjunct therapy is not pursued, the lesion may spread to adjacent structures and subsequently necessitate amputation to prevent systemic metastasis .

Although a retrospective study determined that most foot and ankle tumors are benign , foot and ankle lesions should be approached as malignant until proven otherwise. While EHEs generally have a favorable clinical course, the risk of aggressive lesions is present. Malignant lesions of the foot and ankle may be missed or mischaracterized as routine benign lesions within the foot and ankle, such as bone cysts, hematoma, hemangioma, enchondroma, osteochondroma, etc ^,, . Immunohistochemical and histopathological analyses are essential to differentiate lesions. Carranza-Romero et al. highlights studies showing EHE are immunoreactive for FVIII, CD31, CD34, cytokeratin, smooth muscle actin, and vimentin ^, . Immunohistochemical analysis of EHE must be interpreted with caution since marks are expressed in other lesions. For instance, epithelioid sarcomas express cytokeratin, EMA, and CD34, with the loss of expression of INI1, SMARCB1 . ERG transcription factor, known to be expressed in endothelial cells, may be a useful marker in differential diagnosis ^, . To distinguish EHE from both epithelioid hemangioma and angiosarcoma, which are all immunoreactive for CD31 and CD34, histopathology should be assessed for distinctive characteristics. EHEs typically provide a distinctive myxochondroid to hyalinized matrix, containing small cytologically bland ovoid tumor cells that grow in arrays, strands, and nests ^, . The cases reported in the foot and ankle described above also described the distinct myoxid stroma ^,,, . Also, further differentials that should be considered are listed in Table 1 ^,,,,, . We encourage physicians to thoroughly assess any growth on the lower extremity as potentially dangerous lesions until proven otherwise.

Table 1

Some considerations of differential diagnoses reported by other authors ^,,,,, .

Vascular	Bone/Soft Tissue Tumors	Cutaneous/Joint Lesions
Hematoma	Giant cell tumor	Simple bone cyst
Hemangioma	Soft tissue lipoma	Ganglion cyst
Epithelioid hemangioendothelioma	Osteoid osteoma	Nerve sheath tumor
Pyogenic granuloma	Osteochondroma	Schwannoma
Hamartoma	Endochondroma	Plantar fibromatosis
Arteriovenous malformation	Synovial chondromatosis	Synovial tumors

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