Practice Essentials
Angioendotheliomatosis is a histopathological term characterized by proliferation of cells within vascular lumina with secondary intravascular thrombi and obliteration of the vessels. While angioendotheliomatosis was initially thought to be a single disease entity, recent studies showed that it may be divided into 2 or maybe more variants.
A benign reactive variant (reactive angioendotheliomatosis [RAE]) is a rare and poorly defined disorder characterized by intravascular proliferation of cells expressing endothelial cell markers.
A malignant variant (malignant angioendotheliomatosis [MAE]) is an angiotropic lymphoma mostly of the B-cell phenotype.
Previously, angioendotheliomatosis with cells of histiocytic differentiation have also been described; however, currently this entity is called intralymphatic histiocytosis. This differentiation could possibly be due to the development of more specific immunohistochemical markers. [1, 2, 3]
Intravascular histiocytic cell proliferation may be a neoplastic proliferation of histiocytes (intralymphatic histiocytosis) or an early stage of classic reactive angioendotheliomatosis. The latter represents residual cells associated with the organization of microthrombi, which are later followed by endothelial cell proliferation.
A local variant of reactive angioendotheliomatosis associated with ischemia resulting from arterial occlusion and atherosclerosis has also been described and is called diffuse dermal angiomatosis (DDA). [4, 5, 6, 7] This variant is confined to the ischemic area.
Signs and symptoms
Patients with the malignant and reactive form may have constitutional symptoms at the time of presentation. Patients most commonly complain of low-grade fever and myalgia. Other complaints include the following:
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Chills
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Night sweats
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Weakness
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Weight loss
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Malaise
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Arthralgia
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Depression
Skin papules and nodules that are slowly increasing in size can be painful and tender, sometimes with a burning sensation.
Similar skin lesions can be observed in both the malignant and the reactive forms. [8] Erythematous-to-violaceous macules, papule, nodules, or plaques are often observed in the abdominal region or the lower extremities. The trunk, arms, breasts, and face, including earlobes, can also be affected. The lesions may be indurated, hemorrhagic, or ulcerative. In the reactive form, lesions are always confined to the skin. In the malignant form, the nervous system seems to be the favorite target of the disease. Apart from that, the following organs are most frequently involved: adrenal glands, thyroid, pancreas, lungs, liver, spleen, lymph nodes, heart, stomach, and kidneys. Bone marrow is typically not affected.
In the malignant form, skin lesions are noted in about 30% of the patients. These tend to localize on the lower extremities and the abdomen.
Aguayo-Leiva et al, Rozenblat et al, and Corti et al reported cellulitislike plaques. [9, 10, 11] CNS signs are observed in about 85% of patients. Adrenal gland involvement may lead to hypoadrenalism. Lymph nodes are generally spared; thus, adenopathy is absent.
Patients rarely present first with primary lung or prostate disease, disseminated intravascular coagulation, lytic bone lesions, or panhypopituitarism.
In diffuse dermal angiomatosis, pulses over the arteries located distally from the site of occlusion can be impalpable.
Complications
Cardiovascular risk should be considered. [12] Infarction is a complication if the coronary arteries are involved.
Diagnostics
Also see Workup.
Peripheral blood smear and indices and serum chemistry results are often unremarkable. As for reactive angioendotheliomatosis, the results depend on the underlying disease. The following findings could be observed:
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Anemia
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Elevated erythrocyte sedimentation rate
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Low platelet count
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Leukocytosis/leukopenia
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Elevated lactate dehydrogenase (LDH) levels
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Abnormalities in cold-reactive proteins are sometimes observed (ie, circulating cryoproteins, elevated cryofibrinogen levels).
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Increased alkaline phosphatase levels
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Increased aspartate and alanine aminotransferase levels
Management
Also see Medication.
In malignant angioendotheliomatosis, follow treatment protocols used in lymphoma.
In reactive angioendotheliomatosis, treat the underlying cause if detected.
In diffuse dermal angiomatosis, revascularization may lead to disappearance of lesions. Some response to isotretinoin therapy has been reported.
Posttraumatic reactive angioendotheliomatosis may respond favorably to topical timolol maleate. [13]
Pulsed dye laser treatment may be beneficial. [14]
Consultations
Consider consultations with the following field specialists because of the condition's different presenting symptoms:
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Dermatologist
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Neurologist
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Oncologist
Pathophysiology
The pathogenesis of reactive angioendotheliomatosis is still not fully elucidated. Although the exact stimulus for the proliferation of endothelial cells is not known, occlusion of vascular lumina of different causes seems to be the common feature of this disease. [15, 16] In reactive angioendotheliomatosis, frequent association with systemic infection, subacute bacterial endocarditis, acute otitis media, pulmonary tuberculosis, allergic response to cow's milk protein, arthritis, [17, 18] cryoproteinemias, monoclonal gammopathies, iatrogenic arteriovenous fistulas, antiphospholipid syndrome, [19, 20, 21] severe peripheral vascular atherosclerotic disease, or chronic venous insufficiency, [22] has been reported.
These findings suggest that reactive angioendotheliomatosis represents a hypersensitivity reaction. Probably different stimuli (eg, bacteria, viruses, cryptoproteins) can lead to the vessels occlusion, hypoxemia, and subsequently endothelial cell proliferation. Some authors suggest that reactive angioendotheliomatosis is an unusual residuum of leukocytoclastic vasculitis.
The lesions of malignant angioendotheliomatosis are thought to result from a sludging effect of the circulating malignant lymphoid cells. Fibrin deposits seem to play a role in this process, thus explaining the infarctive symptoms patients may experience. [23]
In diffuse dermal angiomatosis, in which the vessels are partially occluded by atherosclerotic plaques, a local increase of vascular endothelial growth factor (VEGF) caused by hypoxia that can subsequently lead to endothelial cell proliferation is a possible cause. [24] A history of heavy smoking could be regarded as an important factor in diffuse dermal angiomatosis pathogenesis.
Etiology
Different triggers (eg, subacute bacterial endocarditis; circulating immune complexes; fibrin; cholesterol emboli; viruses, such as hepatitis C; atriovenous fistula [25] ; atherosclerotic emboli; trauma; metal implants [26] ; drugs such as trabectedin and pegfilgrastim administered for recurring myxoid liposarcoma [27] ) should be kept in mind in reactive angioendotheliomatosis.
Other reported associations include cryoglobulinemia, [28] graft versus host disease, [29] and erythema ab igne. [30]
In diffuse dermal angiomatosis (a form of reactive angioendotheliomatosis), ischemia induces a local increase of VEGF, a well-known inducer of endothelial cell proliferation. In hypoxia, such situations can occur in different tissues.
Epidemiology
Frequency
About 100 cases of malignant angioendotheliomatosis and about 40 cases of the reactive form have been described worldwide. The first case of RAE was described by Gottron and Nikolowski in 1958. [31]
Sex
Men and women are equally affected by both forms of angioendotheliomatosis.
Age
Most patients presenting with the malignant form are 40-80 years. The average age at onset of the malignant form is about 60 years.
The reactive form has been described in all age groups, from infancy to old age [32] ; however, reactive angioendotheliomatosis is most common in adulthood.
Prognosis
Malignant angioendotheliomatosis is a multisystem disorder that is usually fatal. It has a poor prognosis, with an average survival time of 13 months. In about 80% of patients, a fatal outcome is observed within a year of diagnosis.
In diffuse dermal angiomatosis, after bypass surgery, skin lesions (even ulcerative) demonstrate rapid improvement, with subsequent total healing sometimes leaving residual scarring, usually in 6 weeks maximum.
Reactive angioendotheliomatosis has a good prognosis and usually regresses when the underlying disease, if discovered, is successfully treated. The disease sometimes regresses spontaneously. The prognosis depends on the underlying cause.
