AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Angioendotheliomatosis is divided into variants. A benign reactive variant (RAE) is characterized by a proliferation of cells expressing endothelial cell markers. A malignant variant (MAE) is an angiotropic lymphoma mostly of the B-cell phenotype. Angioendotheliomatosis with cells of histiocytic differentiation have also been described.

Intravascular histiocytic cell proliferation may be a neoplastic proliferation of histiocytes 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 variant of RAE associated with atherosclerosis has also been described and is called diffuse dermal angiomatosis (DDA).

Pathophysiology

The pathogenesis of RAE is still not fully elucidated. Although the exact stimulus for the widespread dermal proliferation of endothelial cells is not known, occlusion of vascular lumina of different causes seems to be the common feature of this disease. In RAE, frequent association with systemic infection, subacute bacterial endocarditis, acute otitis media, pulmonary tuberculosis, allergic response to cow's milk protein, cryoproteinemias, monoclonal gammopathies, iatrogenic arteriovenous fistulas, antiphospholipid syndrome, or severe peripheral vascular atherosclerotic disease has been reported. These findings suggest that RAE 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 MAE 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.

In DDA, 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.

A history of heavy smoking could be regarded as an important factor in DDA pathogenesis.

Frequency

International

About 100 cases of malignant angioendotheliomatosis and less than 30 cases of the reactive form have been described worldwide.

Mortality/Morbidity

• The malignant form 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.
• Reactive angioendotheliomatosis has a good prognosis because it is a self-limited disease; however, recurrences may be observed.

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; however, RAE is most common in adulthood.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Patients with the malignant form may not have any constitutional or neurologic symptoms at the time of presentation. They can complain of only vague symptoms, sometimes of headaches or depression. They tend to have tender cutaneous papules or nodules, which slowly increase in size.

• Patients most commonly complain of low-grade fever and myalgia.
• Other complaints include the following:
• • Chills
  • Night sweats
  • Weakness
  • Weight loss
  • Severe headaches
  • Malaise
  • Arthralgia
  • Depression
• Skin papules and nodules that are slowly increasing in size can be painful and tender, sometimes with a burning sensation.

Physical

Similar skin lesions can be observed in both the malignant form and the reactive form (ie, erythematous-to-violaceous nodules or plaques that can ulcerate). 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.

• Cutaneous erythematous papules (indurated or hemorrhagic) can also present some telangiectasia. The lesions can form plaques or nodules that sometimes ulcerate. They are often observed in the abdominal region or the lower extremities. The trunk; the arms; and the face, including the earlobes, can also be affected.
• Skin lesions are noted in about 30% of the patients. They tend to localize on the lower extremities and the abdomen.
• Edema of the ankles can be observed.
• CNS signs are observed in about 85% of patients. CNS involvement can lead to the following:
• • Dementia
  • Mental sluggishness
  • Cerebrovascular accidents
  • Seizures
  • Peripheral neuropathies
  • Paresthesia
  • Visual disturbances
  • Headaches
  • Other focal neurologic signs
• 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 DDA, pulses over the arteries located distally from the site of occlusion can be impalpable.

Causes

• Different triggers (eg, subacute bacterial endocarditis; circulating immune complexes; fibrin; cholesterol emboli; viruses, such as hepatitis C; atriovenous fistula; atherosclerotic emboli; trauma) should be kept in mind in RAE.
• In DDA (form of RAE), ischemia induces a local increase of VEGF, a well-known inducer of endothelial cell proliferation. In hypoxia, such situations can occur in different tissues.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Angiosarcoma
Acroangiodermatitis
Tufted angioma (angioblastoma)
Mycosis fungoides
Cryoglobulinemia
Perniosis (chilblains)
Phlebitis
Panniculitis
Vasculitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Peripheral blood smear and indices and serum chemistry results are often unremarkable. As for RAE, 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 RAE, 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 DDA, angiography or Doppler ultrasonography can show stenotic changes of the vessels.
• In MAE, 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 MAE.

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 RAE from intravascular lymphoma. 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.

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 DDA, 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• In MAE, follow chemotherapy protocols similar to those used in classic lymphoma treatment.
• In RAE, treat the underlying cause if detected.

Consultations

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

• Dermatologist
• Neurologist
• Oncologist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

Drug Category: Cytotoxic agents

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

Drug Category: Corticosteroids

These agents are used for immunosuppression of malignant cells.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• Infarction is a complication if the coronary arteries are involved.

Prognosis

• MAE is a multisystem disorder that is usually fatal. It has a poor prognosis.
• In DDA, after bypass surgery, skin lesions (even ulcerative) demonstrate rapid improvement, with subsequent total healing sometimes leaving residual scarring, usually in 6 weeks maximum.
• RAE has a good prognosis and usually regresses when the underlying disease, if discovered, is successfully treated. The disease sometimes regresses spontaneously.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to perform a histologic analysis for the diagnosis of angioendotheliomatosis is a pitfall.
• • An excisional biopsy specimen obtained through the depth of the subcutaneous tissue may be necessary to confirm the diagnosis of MAE.
  • If MAE is highly suspected and not seen on initial sections, serial sectioning of the paraffin block is necessary because the changes may be focal and segmental.
• Failure to consider the diagnosis of MAE is a pitfall. Consider a diagnosis of MAE when examining a patient with tender, indurated nodules, especially when the patient presents with some neurologic complaints.
• Failure to recognize that DDA may be a unique cutaneous manifestation of peripheral atherosclerosis is a pitfall.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Rieger E, Soyer HP, Leboit PE, et al. Reactive angioendotheliomatosis or intravascular histiocytosis? An immunohistochemical and ultrastructural study in two cases of intravascular histiocytic cell proliferation. Br J Dermatol. Mar 1999;140(3):497-504. [Medline].
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Article Last Updated: Feb 6, 2007