Angioendotheliomatosis 

Updated: Apr 28, 2020
Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD 

Overview

Background

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 two 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.

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.[8, 9] In reactive angioendotheliomatosis, frequent association with systemic infection, subacute bacterial endocarditis, acute otitis media, pulmonary tuberculosis, allergic response to cow's milk protein, arthritis,[10, 11] cryoproteinemias, monoclonal gammopathies, iatrogenic arteriovenous fistulas, antiphospholipid syndrome,[12, 13] severe peripheral vascular atherosclerotic disease, or chronic venous insufficiency,[14] 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.[15]

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.[16] 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[17] ; atherosclerotic emboli; trauma; metal implants[18] ; drugs such as trabectedin and pegfilgrastim administered for recurring myxoid liposarcoma[19] ) should be kept in mind in reactive angioendotheliomatosis.

Other reported associations include cryoglobulinemia,[20] graft versus host disease,[21] and erythema ab igne.[22]

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.[23]

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[24] ; 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.

 

Presentation

History

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:

  • Chills

  • Night sweats

  • Weakness

  • Weight loss

  • Malaise

  • Arthralgia

  • Depression

Skin papules and nodules that are slowly increasing in size can be painful and tender, sometimes with a burning sensation.

Physical Examination

Similar skin lesions can be observed in both the malignant and the reactive forms.[25] 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. They tend to localize on the lower extremities and the abdomen.

Aguayo-Leiva et al, Rozenblat et al, and Corti et al reported cellulitislike plaques.[26, 27, 28] 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

Infarction is a complication if the coronary arteries are involved.

 

DDx

Diagnostic Considerations

Also consider the following:

One must consider other painful cutaneous tumors, including leiomyomas, angiolipomas, and glomus tumors.[32]

Differential Diagnoses

 

Workup

Laboratory Studies

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:

  • Anemia

  • Elevated erythrocyte sedimentation rate

  • Low platelet count

  • Leukocytosis/leukopenia

  • Elevated lactate dehydrogenase (LDH) levels

  • Abnormalities in cold-reactive proteins are sometimes observed (ie, circulating cryoproteins, elevated cryofibrinogen levels).

  • Increased alkaline phosphatase levels

  • Increased aspartate and alanine aminotransferase levels

Imaging Studies

In reactive angioendotheliomatosis, echocardiograms, electrocardiograms, and chest radiographs can reveal changes related to the underlying disease (eg, in subacute bacterial endocarditis [SBE], tuberculosis, chronic infection, autoimmune disease).

In diffuse dermal angiomatosis, angiography or Doppler ultrasonography can show stenotic changes of the vessels.

In malignant angioendotheliomatosis, cranial computed tomography and magnetic resonance imaging can frequently demonstrate parenchymal hypodensity consistent with cerebral infarction or a degenerative process.

In bone technetium scintigraphy, results can be normal because bone marrow is typically spared.

Chest radiographs often do not reveal any abnormalities.

Ultrasonography of the abdomen and the pelvis may demonstrate hepatomegaly and splenomegaly; however, no evidence of lymph node involvement exists in the vast majority of patients.

Procedures

Bone marrow biopsy can be totally normal or demonstrate only benign reactive hyperplasia or, in some cases, a malignant lymphoid proliferation compatible with malignant angioendotheliomatosis.[33]

Histologic Findings

Dilated dermal and upper subcutaneous fat blood vessels filled with cells and fibrin thrombi may be observed, with occlusion sometimes being evident. In the reactive form, the cells filling the vessels vary in size from small to large, are bland with open chromatin, and contain inconspicuous nucleoli.

Immunohistochemistry is considered the definitive test used to differentiate reactive angioendotheliomatosis from intravascular lymphoma. In reactive variant, immunocytochemistry of intravascular cells demonstrates positivity for Ulex europaeus I lectin and factor VIII–associated antigen (CD31 and CD34), thus the supporting endothelial origin of the cells. Proliferation of pericytic myoepithelial cells is sometimes noted within and around affected blood vessels.[34]

In the malignant form, a proliferation of atypical, hyperchromatic lymphoid cells with numerous mitotic figures predominates. On immunocytochemistry, cells are positive for lymphocyte markers, such as leukocyte common antigen (CLA, CD45RB), and B-cell (CD20, CD45RA, CD79a) and T-cell (CD1, CD3, CD4, CD8, CD43, CD45RO) markers. Most vessels are surrounded by a perivascular infiltrate containing a large number of plasma cells.

In the histiocytic variant, intraluminal proliferation of cell-bearing histiocyte markers, such as Mac387 and KP1 (CD68), can be observed.

In diffuse dermal angiomatosis, lesions are full of diffuse, extravascular proliferations of endothelial cells between collagen bundles of the reticular dermis, with only minimal intravascular proliferation of those cells. Immunoperoxidase studies using CD31 and CD34 markers highlighted the vessels, confirming the vascular nature of the disease.

 

Treatment

Medical Care

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.

Consultations

Consider consultations with the following field specialists because of the condition's different presenting symptoms:

  • Dermatologist
  • Neurologist
  • Oncologist
 

Medication

Medication Summary

No specific treatment exists for the reactive form. Therapy is focused on the underlying disease, if any. For the malignant form, promptly initiate chemotherapy after making the diagnosis.

Antineoplastics, Other

Class Summary

Chemotherapy protocols similar to that applied in classic lymphoma or leukemia treatment are a widely accepted method of medical intervention.

Cyclophosphamide

Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Cyclophosphamide may be administered at 50-100 mg/m2/d PO or 400-1000 mg/m2 PO in divided doses every 4-5 days; alternatively, administer 400-1800 mg/m2 (30-40 mg/kg) IV in divided doses over 2-5 days; this may be repeated at 2- to 4-week intervals; 10-15 mg/kg IV q7-10d or 3-5 mg/kg bid.

Doxorubicin (Adriamycin)

Doxorubicin inhibits topoisomerase II and produces free radicals, which may cause the destruction of DNA. The combination of these 2 events can, in turn, inhibit the growth of neoplastic cells. Doxorubicin may be administered at 60-75 mg/m2 IV as a single dose; repeat q21d. Alternatively, administer 20-30 mg/m2/d IV for 2-3 d; repeat in 4 weeks in adults. In children, it may be administered at 35-75 mg/m2 IV as a single dose; repeat q21d. Alternatively, administer 20-30 mg/m2 IV qwk.

Vincristine (Vincasar PFS)

The mechanism of action is uncertain, but it may involve a decrease in reticuloendothelial cell function or an increase in platelet production; however, neither of these mechanisms would fully explain the effect in TTP and HUS. Vincristine may be administered at 2 mg IV push in adults. Administer 1.4 mg/m2 IV push, not to exceed 2 mg, in children.

Corticosteroids

Class Summary

These agents are used for their immunosuppressant effects.

Prednisone

Prednisone is an immunosuppressant for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production. It may also cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance. Alternative corticosteroids may be used in equivalent dosages.

Prednisone may be administered at 5-60 mg/d PO qd or divided bid/qid; taper over 2 weeks as symptoms resolve in adults. In children, it may be administered at 4-5 mg/m2/d PO; alternatively, administer 0.05-2 mg/kg PO divided bid/qid; taper over 2 weeks as symptoms resolve.

Prednisolone (Orapred, Pediapred, Millipred)

Prednisolone is an immunosuppressant for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisolone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production. It may also cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance. Alternative corticosteroids may be used in equivalent dosages.

Prednisolone may be administered at 5-60 mg/d PO qd or divided bid/qid; taper over 2 weeks as symptoms resolve in adults. In children, prednisolone may be administered at 4-5 mg/m2/d PO; alternatively, administer 0.05-2 mg/kg PO divided bid/qid; taper over 2 weeks as symptoms resolve.

Retinoid-like Agents

Class Summary

Decreased cohesiveness of abnormal hyperproliferative keratinocytes may reduce potential for malignant degeneration. Retinoids modulate keratinocyte differentiation and have been shown to reduce risk of skin cancer formation.

Isotretinoin (Amnesteem, Claravis, Sotret)

Isotretinoin is an oral agent that treats serious dermatologic conditions. Isotretinoin is the synthetic 13-cis isomer of the naturally occurring tretinoin (trans -retinoic acid). Both agents are structurally related to vitamin A. Isotretinoin decreases sebaceous gland size and sebum production. It may inhibit sebaceous gland differentiation and abnormal keratinization.

A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

Single cases of diffuse dermal angiomatosis have responded to treatment. A dose of 0.5 mg/kg is suggested.