Endovascular Papillary Angioendothelioma

Etiology

Endovascular papillary angioendothelioma may appear de novo or arise within an area of chronic lymphedema or a preexisting vascular malformation such as a hemangioma or a lymphangioma circumscriptum, etc.[3][4][5] The common differentials include retiform hemangioendothelioma, angiosarcoma, reactive angioendotheliomatosis, and benign intravascular endothelial hyperplasia.[6] 

A lymphatic origin for this entity has been proposed due to common morphologic and immunophenotypic findings between adjacent lymphatics and lymphangioma in EPA, as well as the expression of vascular endothelial growth factor and lymphatic immunohistochemical marker, D2-40.[7]

Epidemiology

The Dabska tumor was originally described by Dabska et al. in 1969 in a case series with six patients, all children.[2] Since then, less than 40 cases have been described in the literature. These reported cases show no clear gender predilection, and approximately 75% of patients are children; however, it has also been reported in the elderly.[8] A case series of 12 patients showed an age range of 8-59 with a mean of 30 years, suggesting a wider range.[9] Although it usually presents as an intradermal lesion, there have been reports of involvement of the spleen, testicle, tongue, and bone.[10][11][12][13]

Pathophysiology

Endovascular papillary angioendothelioma is within a borderline area between benign lesions such as hemangioma and malignant ones like angiosarcoma. There have been cases of these tumors arising within preexisting vascular lesions such as cavernous hemangiomas. Morphologic similarity has also been observed with retiform hemangioendothelioma and may represent the spectrum of the same lesion. Based on the literature review, currently, the diagnosis of EPA is limited to low-grade sarcoma, demonstrating characteristic histopathological and immunohistochemistry features.[6]

Histopathology

Histopathological evaluation remains a gold standard for the diagnosis of these rare tumors. They are characterized by numerous interconnecting vascular channels with papillary projections or tuft like structures as observed in renal glomeruli. Endothelial cells lining the vascular channels have a classic hobnail or matchstick appearance due to an apically placed nucleus that produces a surface bulge.[11][14] Also, these cells demonstrate a high nuclear to cytoplasmic ratio with mitotic activity to a moderate degree.[14] Intravascular and perivascular lymphocytic infiltrates have also been observed.[6] Among all these features, the demonstration of papillary projections seems to be the most important for the diagnosis of endovascular papillary angioendothelioma.

Immunohistochemistry further aids in diagnosis by identifying the tissue origin. EPA tumor cells react positively to vascular and lymphatic markers. They are classically positive for CD34, VEGFR - 3, CD31, D2-40, and factor VIII related antigen.[6] D2-40 is a lymphatic endothelial marker; its positivity differentiates it from other tumors exhibiting similar characteristics on histology.[6]

Small storage granules consisting of von Willebrand factor and P-selectin, called Weibel Palade bodies, might be demonstrated upon examination under the electron microscope of the tumor cells. Also seen are irregular nuclei, abundant perinuclear cytoplasmic filaments, and pinocytotic vesicles.[11]

History and Physical

Generally, endovascular papillary angioendothelioma presents as a slow-growing, painless nodule that is typically localized to the subcutaneous tissue of the extremities, dermis, and less commonly on the trunk, head, and neck.[11] Some cases have been reported in deeper locations such as the bone, brain, spleen, tongue, and testis.[8] Notably, no other primary sources were discovered in these instances, nor was lymph node involvement identified.[6]

Most cutaneous tumors come to medical attention when they are two to three centimeters in size.[15] However, much larger lesions have been reported, and have been seen up to 40 centimeters in diameter. The tumors may vary in appearance. Some are described as an ill-defined mass, a plaque, or a nodule with projections into the surrounding tissue. The overlying skin may be pink, blue, or violaceous in color with an atrophic dermis.

Symptomatology is also variable. Patients may complain of pain, ulceration, or bleeding from the affected site.[6] Though these lesions tend to be low grade, cases of regional nodal involvement and pulmonary metastasis have been reported in the literature.[16] Hence, it is essential for complete physical evaluation, including a metastatic workup.

Evaluation

The definitive diagnosis of EPA is made with a biopsy. As this is such a rare entity, protocols for disease involvement, surveillance, and follow-up have yet to be established. It is reasonable to consider obtaining a chest radiograph for any patient with pulmonary symptoms due to a reported case of a patient dying of pulmonary metastases. Lymph node examination may be performed if there is suspicion for involvement.[15]

Treatment / Management

Surgical excision is recommended. In general, the prognosis is favorable for Dabska tumors even with invasion into deeper structures. However, the malignant potential of this tumor should not be ignored, and close follow-up should be maintained.[6] Regional lymphadenectomy should be performed when those structures appear involved.[15](B3)

In one case report, the authors chose to follow National Comprehensive Cancer Network (NCCN) practice guidelines in oncology for soft tissue sarcoma of extremity/trunk stage IIA (T1bN0M0G2), which recommends chest imaging (plain radiograph or chest computed tomography) every 3 to 6 months for 2 to 3 years, then every six months for two years, and then annually for ongoing monitoring.[6](B3)

Differential Diagnosis

The differential diagnosis of this tumor is histologic, as many neoplasms display intravascular proliferation. The differential should include intravascular papillary endothelial hyperplasia (Masson tumor), epithelioid hemangioendothelioma, angiosarcoma, lymphangioma-like Kaposi sarcoma, and retiform hemangioendothelioma.[7]

The unique feature of EPA is the papillary structure lined by atypical columnar endothelial cells. A similar formation has been described extravascularly in the patch stage Kaposi sarcoma. Ordinary angiosarcomas may also show focal morphologic patterns of EPA, and in a study of 80 cases of angiosarcoma of soft tissue, 14% showed evidence papillary fronds.[16] Angiosarcoma, however, shows more significant endothelial atypia and diffuse growth outside of blood vessels.[7]

Organized thrombi cause the Masson phenomenon, showing papillary processes of the fibrous cores covered with a layer of endothelial cells. Unlike EPA, the Masson phenomenon is contained within blood vessels, and there are often visible intravascular thrombi. It lacks the presence of columnar endothelial cells and has a single endothelial cell layer surrounding hyalinized stromal cores.[7]

Epithelioid hemangioendothelioma display endothelial cells with eosinophilic vacuolated cytoplasm. The tumor cells arrange as cords, trabeculae, or sheets with myxoid or hyalinized stroma, and often spread outside of the blood vessel.[7]

Of note, there have been reports in the literature of benign acquired vascular proliferations displaying areas with Dabska features simulating malignancy. Therefore, the presence of atypical architectural features in an otherwise benign-looking acquired vascular proliferation should not lead to unnecessarily aggressive treatment.[17]

Surgical Oncology

Currently, wide local excision remains the treatment of choice for these tumors.[16] In most of the patients, this treatment is sufficient without any recurrence. However, a few cases of lymph nodal involvement and pulmonary metastasis have been reported, thus advocating the need for close follow up and long term evaluation.[16]

Radiation Oncology

Evidence for radiation therapy in these tumors is limited. Of the six patients reported by the Dabska et al. group, three received radiation therapy; of these, two received preoperative radiation while one received it after surgery.[14] Those who received preoperative radiation did not report any response; however, this could be due to the suboptimal dose delivered to these patients. The recommended radiation dose in the preoperative setting for sarcomas is around 50Gy, and the dose they received was around 30Gy. Currently, there are no recommendations for radiation therapy; however, due to deep invasion features observed, it may play a role in the recurrent setting.

Due to the rarity of these tumors, the benefit of radiation therapy in a randomized trial would be difficult to obtain. Hence it would be prudent to consider radiation in tumors showing features of a high risk of recurrences such as size > 5 cm, deep invasion, and positive margins based upon their behavior pattern similar to low-grade sarcomas.

Pertinent Studies and Ongoing Trials

Due to the rarity of these tumors, it is challenging to obtain level I evidence for treatment recommendations. Currently, the practice guidelines are obtained from published case series and reports.

Treatment Planning

Patterns of failure are yet to be determined for this rare tumor; meanwhile, it would be prudent to consider radiation in a post-operative setting for tumors exhibiting high-risk features for recurrence. Dose, technique, and volume delineation should be based on the principles of radiation therapy in sarcoma.

Medical Oncology

Based on the literature review, the role of systemic therapy remains yet to be established. Chemotherapy has shown response in angiosarcomas; there may be a role for chemotherapy in the metastatic setting.[18] It is highly recommended for institutions to report their experience with radiation therapy and systemic therapy, which will further add to the literature and guide others in treating these rare tumors with the best possible approach.

Prognosis

In general, endovascular papillary angioendothelioma are low-grade tumors with favorable outcomes managed with surgery alone. Long term review of originally described patients with Dabska tumors has reported excellent outcomes.[14] However, lymph node metastasis and pulmonary metastasis have been documented, so close follow up and evaluation is warranted.[16]

Complications

Endovascular papillary angioendothelioma are slow-growing tumors with favorable prognosis. However, there have been reports of pulmonary metastasis; hence these tumors are not to be underestimated and should be evaluated and treated in time.