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Background
Reactive angioendotheliomatosis (RAE) is a benign cutaneous vascular disorder characterized by a distinct histologic and clinical appearance. Reactive angioendotheliomatosis is associated with several disorders, including infectious diseases (especially subacute endocarditis), antiphospholipid syndrome, dysglobulinemia, and cryoproteinemia.
OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION AMYLOID Reactive Angioendotheliomatosis Secondary to Dermal Amyloid Angiopathy
Nicolas Ortonne, M.D.; Marie-Dominique Vignon-Pennamen, M.D.; Ghandour Majdalani, M.D.; Laure Pinquier, M.D.; Anne Janin, M.D.
From the Department of Pathology, Hôpital Saint-Louis, Paris (N.O., M.-D. V.-P., L.P. A.J.), and Department of Nephrology and Hemodialysis, Center Hospitalier Général d'Evreux, Evreux (G.M.), France.
Am J Dermatopathol 2001;23:315-319 Abstract quote
Reactive angioendotheliomatosis (RAE) is a rare benign cutaneous vascular proliferation characterized by intravascular hyperplasia of endothelial cells and tuft-like proliferation of vessels.
A 75-year-old man had erythematous and violaceous macules, some stellate and others arranged in a livedoid pattern, evolving toward necrosis with central areas having an ``atrophie blanche'' appearance spread on the trunk, inguinal folds, and right thigh. He was on hemodialysis and had a benign monoclonal gammopathy. Cutaneous biopsy revealed RAE characterized by the proliferation of epithelioid and spindle-shaped cells in superficial and middermis lining vascular channels, arranged in clusters, and sometimes displaying an intravascular growth pattern. These cells stained for CD31, CD34, and actin. Interestingly, prominent amyloid deposits were found in the wall of some vessels in deep dermis, often causing obstruction of their lumina.
The cause of RAE is unknown, but it can be associated with infections, antiphospholipid syndrome, dysglobulinemia, cryoproteinemia, and lower extremities arteritis, and it may occur near arteriovenous fistulas. In this patient, we believe that RAE was caused by obliteration of dermal vessels by amyloid deposits. Indeed, it is thought that RAE could be caused by ischemia secondary to vascular obstruction.
This is the first reported patient with RAE associated with amyloid deposits.
ANGIOSARCOMA
- Reactive angioendotheliomatosis in association with a well-differentiated angiosarcoma.
Clarke LE, Julian KG, Clarke JT, Ioffreda MD.
Department of Pathology, The Penn State College of Medicine/Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
Am J Dermatopathol. 2005 Oct;27(5):422-7. Abstract quote
A 55-year-old white female with a complex medical history including mixed connective tissue disease and peripheral vascular disease developed a group of red-purple papules on her proximal medial thigh that was followed, five months later, by the development of a large violaceous patch.
She reported a history of radiation to this site (for melanoma) during her childhood. She was admitted to the hospital with a presumptive diagnosis of cellulitis, but failed to respond to antibiotics.
A biopsy was performed and demonstrated a well-differentiated angiosarcoma arising in conjunction with reactive angioendotheliomatosis. Excision of the lesion was performed, and fifteen months of follow-up have shown no recurrence or metastasis.ARTERIOVENOUS FISTULAS
Intravascular and diffuse dermal reactive angioendotheliomatosis secondary to iatrogenic arteriovenous fistulas.Requena L, Farina MC, Renedo G, Alvarez A, Yus ES, Sangueza OP.
Department of Dermatology, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain.
J Cutan Pathol 1999 Mar;26(3):159-64 Abstract quote Reactive angioendotheliomatosis is a rare benign process that has been mainly described in patients with systemic infections, such as subacute bacterial endocarditis or tuberculosis, and in association with intravascular deposition of cryoproteins.
Histopathologically, it is characterized by a proliferation of endothelial cells within vascular lumina resulting in the obliteration of the involved vessels. Another rare variant of reactive angioendotheliomatosis has been described in the lower extremities of patients with severe peripheral vascular atherosclerotic disease. It consists of violaceous and purpuric plaques histopathologically characterized by diffuse proliferation of endothelial cells interstitially arranged between collagen bundles of the reticular dermis. This second variant has been named diffuse dermal reactive angioendotheliomatosis.
We report two patients with reactive cutaneous angioendotheliomatosis appearing distally to arteriovenous fistulas used for hemodialysis because of chronic renal failure. The first patient showed intravascular reactive angioendotheliomatosis, while the second one had purpuric plaques that were characterized histopathologically by diffuse dermal angioendotheliomatosis.
Both patients showed an arteriovenous "steal" syndrome with distal ischemia, and it is possible that a local increase of vascular endothelial growth factor, as is the case in hypoxia situations, induces the endothelial proliferation. To the best of our knowledge, cutaneous reactive angioendotheliomatosis has not been previously described in association with arteriovenous shunts.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL VARIANTS INFANTILE
Reactive angioendotheliomatosis in an infant.Brazzelli V, Baldini F, Vassallo C, Borghini F, Chiesa MG, Rosso R, Borroni G.
Department of Human and Hereditary Pathology, Institute of Dermatology and Pathology, University of Pavia, Policlinico S. Matteo IRCCS, Italy.
Am J Dermatopathol 1999 Feb;21(1):42-5 Abstract quote Reactive cutaneous angioendotheliomatosis (RCA) is an uncommon benign disease characterized by intravascular proliferation of endothelial cells. The observation of RCA in infants is exceedingly rare.
We describe a case of RCA in a 3-month-old infant. The lesions were characterized by six small purpuric papules (1-2 mm in diameter), distributed on the thighs and neck. The general condition of the patient was good, with no lymphadenopathy, systemic involvement, or fever. The histopathologic features of a papule were characterized by the presence of cohesive aggregates of large mononucleated cells protruding into the lumina of dilated vessels and filling some of them completely. Neither an inflammatory infiltrate nor a proliferation of pericytes were present around blood vessels.
Intravascular proliferating cells demonstrated positive staining for Ulex europaeus agglutinin 1 (UEA-1) and for Factor VIII-RA and CD34 antigens. The course of the disease was unremarkable with persistence of the lesions for 8 months; no treatment was started.
INTESTINES Reactive Angioendotheliomatosis of the Intestine
Ogawa, Kumiko MD*; Tada, Toyohiro MD†; Takeuchi, Yuuki MD‡; Suenaga, Masahiro MD‡; Suzuki, Shugo MD*; Shirai, Tomoyuki MD*
From the *Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; †Department of Pathology, Nagoya City University School of Nursing, Nagoya, Japan; and ‡Department of Surgery, Nagoya Memorial Hospital, Nagoya, Japan.
The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 257-261 Abstract quote We present a case of reactive angioendotheliomatosis (RAE) of the colon, featuring intravascular proliferation of endothelial cells with histologic resemblance to glomeruloid hemangioma. A 19-year-old Japanese male with an anal fistula was diagnosed endoscopically with Crohn's disease. Six months later, he was hospitalized for fever and abdominal pain. Emergency resection of ileocecum and splenic flexure of the colon was undertaken to control massive intestinal hemorrhage, and in all parts of the resected colon, foci of many small vessels with intravascular proliferation of endothelial cells were noted throughout the layers. Moreover, solid proliferation of endothelial cells was seen in the submucosa at the base of open ulcers. Two small granulomas, compatible with Crohn's disease, were also evident in the muscle layer of the terminal ileum. No other hemangiomas or hemangioma-like structures were observed with CT scans, and the vascular lesions were histologically diagnosed as RAE. The pathogenesis of this disorder is unknown, and most cases occur in skin with systemic disease. The present case might thus be a first case of RAE of the intestine without cutaneous involvement. Whether there is a relation with coexistent enteritis suggestive of Crohn's disease needs to be clarified.
Vascular proliferative lesions in the gastrointestine include tumors and tumor-like conditions of the blood vessels. One of the pathologic problems in classifying these lesions is that it is often difficult to distinguish between true tumors and congenital or acquired disorders.11 However, in either case, there is clinical importance since they are possible causes of massive intestinal hemorrhage.
We present here a case of multifocally observed hemangioma-like lesions featuring intravascular proliferation of endothelial cells in the ascending and descending colon, histologically compatible with reactive angioendotheliomatosis (RAE). RAE is an uncommon disorder most frequently found in the skin. To our knowledge of the literature, this is the first case report of RAE affecting the intestine. The pathogenesis of RAE is unknown, and the etiological significance of coexistent Crohn's disease-like enteritis remains to be defined.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL Intravascular and extravascular hyperplasia of endothelial and myoepithelial cells in the dermis
Reactive angioendotheliomatosis: a study of 15 cases demonstrating a wide clinicopathologic spectrum.McMenamin ME, Fletcher CD.
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, U.S.A.
Am J Surg Pathol 2002 Jun;26(6):685-97 Abstract quote Reactive angioendotheliomatosis (RAE) is a rare condition characterized by cutaneous vascular proliferation that usually occurs in patients with diverse types of coexistent systemic disease. Although intravascular proliferation of endothelial cells has been considered to be the key histologic feature in RAE, other patterns of vascular proliferation have also been described.
We reviewed the clinicopathologic features in 15 cases of RAE. The study group comprised eight males and seven females with an age range of 47-88 years (median 65 years). Eleven patients had coexistent systemic disease: renal disease (six patients, including three post renal transplantation); valvular cardiac disease (two patients); one patient each had alcoholic cirrhosis, glioblastoma multiforme (on chemotherapy), and rheumatoid arthritis/polymyalgia rheumatica. Six patients were iatrogenically immunosuppressed at the onset of the skin lesions.
The clinical appearance included multiple erythematous macules, plaques, tumors, and ulcerated lesions, with a wide distribution but a propensity to involve limbs. Lesions had been present for 1 month to 4 years (median 4 months). Lesions resolved in four cases, improved in two cases, remained static in one case, and progressed in four cases. Two cases were recent and follow-up was not available in two other cases. Three patients died of their coexistent systemic disease with resolution, improvement, and progression of lesions, respectively. All lesions were characterized histologically by a proliferation of capillaries in the dermis, with variably diffuse (seven cases), lobular (six cases), or mixed lobular and diffuse patterns (two cases). There was marked intercase and intracase heterogeneity in histologic features.
Common features included fibrin microthrombi (nine cases), reactive (fasciitis-like) dermal alterations (seven cases), and foci of epithelioid endothelium (four cases). Four of 10 cases tested showed positive immunohistochemical staining for HHV-8 latent nuclear antigen in lesional endothelial cell nuclei.
This study suggests that RAE has a broader clinicopathologic spectrum than previously described. The pathogenesis of this rare disorder is unknown, but it is likely that immunologic factors play a role.
VARIANTS DIFFUSE DERMAL ANGIOMATOSIS
- Diffuse Dermal Angiomatosis: A Previously Undescribed Pattern of Immunoglobulin and Complement Deposits in Two Cases.
Quatresooz P, Fumal I, Willemaers V, Cornil F, Pierard GE.
*Department of Dermatopathology, University Hospital Sart Tilman daggerDepartment of Dermatology, Citadelle Medical Centre, Liege, Belgium.
Am J Dermatopathol. 2006 Apr;28(2):150-154. Abstract quote
Two cases of diffuse dermal angiomatosis are reported in middle-aged women. This rare disease of unknown origin is characterized by increased dermal angiomatosis and ulceration. The clinical and histologic presentations of the presently reported lesions were typical for this disorder. Endothelial cells exhibited a normal immunophenotype. The perivascular basement membranes showed a distribution of collagen alpha chains typical for blood vessels, but not for lymphatics. Immunohistochemistry revealed other undescribed features.
At the site of the clinical lesions, linear and granular deposits of immunoglobulins A and M, and complement were found around the vessels and at the dermal-epidermal junction. The same deposits were also found restricted to the dermal-epidermal junction in the peripheral clinically intact skin. No serological signs of auto-immune disorder were detected in one patient. A monoclonal gammopathy was disclosed in the other patient. A pattern of immunoreactant deposits similar to that disclosed in the two patients was not found in the control specimens, and has not been described so far in other types of vascular hyperplasia and neoplasia.
A pathogenic role of these deposits is unsettled and should be further explored.
Diffuse dermal angiomatosis: a variant of reactive cutaneous angioendotheliomatosis.Krell JM, Sanchez RL, Solomon AR.
Department of Dermatology, Emory University School of Medicine, Atlanta, GA 30322.
J Cutan Pathol 1994 Aug;21(4):363-70 Abstract quote Reactive angioendotheliomatosis (RA) is a rare, benign disease. Affected patients present with self-limited, erythematous to violaceous plaques. The clinical lesions are due to intravascular hyperplasia of cytologically banal endothelial cells in the dermis.
We report 2 patients who presented with ulcerated, violaceous plaques on the lower extremities. Both had severe peripheral vascular atherosclerotic disease requiring bypass grafts. Unlike previously described cases of RA, our patient's lesions were due to a diffuse proliferation of endothelial cells in the reticular dermis with only minimal, focal intravascular proliferation of these cells.
Positive immunostaining with antibodies to Factor VIII-related and CD34 antigens adds evidence that the proliferated cells in the dermis were endothelial cells.
Intravascular and diffuse dermal reactive angioendotheliomatosis secondary to iatrogenic arteriovenous fistulas.Requena L, Farina MC, Renedo G, Alvarez A, Yus ES, Sangueza OP.
Department of Dermatology, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain.
J Cutan Pathol 1999 Mar;26(3):159-64 Abstract quote Reactive angioendotheliomatosis is a rare benign process that has been mainly described in patients with systemic infections, such as subacute bacterial endocarditis or tuberculosis, and in association with intravascular deposition of cryoproteins.
Histopathologically, it is characterized by a proliferation of endothelial cells within vascular lumina resulting in the obliteration of the involved vessels. Another rare variant of reactive angioendotheliomatosis has been described in the lower extremities of patients with severe peripheral vascular atherosclerotic disease. It consists of violaceous and purpuric plaques histopathologically characterized by diffuse proliferation of endothelial cells interstitially arranged between collagen bundles of the reticular dermis. This second variant has been named diffuse dermal reactive angioendotheliomatosis.
We report two patients with reactive cutaneous angioendotheliomatosis appearing distally to arteriovenous fistulas used for hemodialysis because of chronic renal failure. The first patient showed intravascular reactive angioendotheliomatosis, while the second one had purpuric plaques that were characterized histopathologically by diffuse dermal angioendotheliomatosis. Both patients showed an arteriovenous "steal" syndrome with distal ischemia, and it is possible that a local increase of vascular endothelial growth factor, as is the case in hypoxia situations, induces the endothelial proliferation.
To the best of our knowledge, cutaneous reactive angioendotheliomatosis has not been previously described in association with arteriovenous shunts.
Diffuse dermal angiomatosis of the breast: response to isotretinoin.
McLaughlin ER, Morris R, Weiss SW, Arbiser JL.
Department of Dermatology, Emory University School of Medicine, 1639 Pierce Dr., Atlanta, GA 30322, USA.
J Am Acad Dermatol 2001 Sep;45(3):462-5 Abstract quote Dermal angiomatosis of the breast is an extremely rare disorder of unknown origin characterized by increased angiomatosis and ulceration.
We report a case of a young woman whose disorder responded to isotretinoin. Our findings have potential relevance to the treatment of skin disorders in which ulceration is a prominent feature.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE
Reactive and malignant "angioendotheliomatosis": a discriminant clinicopathological study.Wick MR, Rocamora A.
Department of Pathology, University of Minnesota School of Medicine, Minneapolis.
J Cutan Pathol 1988 Oct;15(5):260-71 Abstract quote In order to determine whether or not phenotypic differences existed between reactive angioendotheliomatosis (RAE) and malignant angioendotheliomatosis (MAE), we studied the histological and immunohistochemical features of 4 and 8 cases of these lesions, respectively.
Antibodies to leukocyte common antigen (LCA), specialized B- and T-lymphocytic determinants, Factor VIII-related antigen (FVIIIRAG), blood group isoantigens A, B, and H (BGI), epithelial antigens, vimentin, and actin; and Ulex europaeus I lectin (UEL) were utilized. Cutaneous lesions in all cases of MAE were part of a disseminated, fatal, intravascular cellular proliferation, with highly atypical cytological features. Because one of the patients in this group had cardiac valvular vegetations at autopsy, this case had been reported previously as representative of RAE.
However, the latter example, as well as all others of MAE, stained strongly for LCA, B-cell antigens, and vimentin in tumor cells. FVIIIRAG was seen focally in 6 cases, in cells entrapped in platelet-fibrin thrombi; however, UEL binding and reactivity for BGI were uniformly absent. Conversely, RAE was typified by a cytologically-bland intravascular proliferation, with actin-positive, perivascular, pericytic cuffs. All 4 patients in this group had cutaneous involvement only, and the lesions tended to be self-resolving. One had pulmonary tuberculosis, but evidence for an underlying infection was absent in the remainder of RAE cases. Immunohistologically, RAE displayed universal reactivity for FVIII-RAG, BGI, UEL, and vimentin, and negativity for LCA in intravascular cells. Neither MAE nor RAE showed the presence of epithelial determinants.
These data indicate that MAE and RAE are clinicopathologically distinct entities, showing lymphoid and endothelial features, respectively. Because of the phenotypic properties of the former condition, it would appear advisable to substitute the term "intravascular lymphomatosis" for "malignant angioendotheliomatosis".
Reactive angioendotheliomatosis or intravascular histiocytosis? An immunohistochemical and ultrastructural study in two cases of intravascular histiocytic cell proliferation.Rieger E, Soyer HP, Leboit PE, Metze D, Slovak R, Kerl H.
Department of Dermatology, University of Graz, Auenbruggerplatz 8, A-8036 Graz, Austria.
Br J Dermatol 1999 Mar;140(3):497-504 Abstract quote Two elderly women with complex medical histories presented with erythematous patches, in one case involving the face and forearms, and in the other both elbows. Punch biopsies from both patients revealed intravascular proliferations of medium-sized and large cells with luminal occlusion typical of angioendotheliomatosis. Immunostaining did not show either lymphocytic or endothelial cell antigens but was consistent with a histiocytic differentiation of the intravascular cells in both cases, and was further substantiated by ultrastructural examination in one case.
One patient received a course of cyclophosphamide therapy over 15 days. Skin lesions faded but did not disappear. The patient died 10 months later from cardiac and renal failure, which was most probably unrelated to the skin lesions. In the other case, lesions diminished but did not entirely resolve with treatment with low doses of oral prednisone. Angioendotheliomatosis can be divided into a malignant variant, which is an angiotropic lymphoma mostly of B-cell phenotype, and a benign, reactive variant, which is characterized by a proliferation of cells expressing endothelial cell markers. Only one case of angioendotheliomatosis with cells of histiocytic differentiation has been published previously under the name of intravascular histiocytosis. Our cases are very similar to the latter.
The question arises as to whether intravascular histiocytic cell proliferation is a neoplastic proliferation of histiocytes or an early stage of classic reactive angioendotheliomatosis representing the residual cells associated with organization of microthrombi, which will be later followed by endothelial cell proliferation.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES EPITHELIOID HEMANGIO-ENDOTHELIOMA
Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases.Mentzel T, Beham A, Calonje E, Katenkamp D, Fletcher CD.
Department of Pathology, University of Jena, Germany.
Am J Surg Pathol 1997 Apr;21(4):363-74 Abstract quote Epithelioid hemangioendothelioma of soft tissues (EHE) represents a distinct entity with an unpredictable clinical course.
We analyzed the clinicopathologic and immunohistochemical features in a series of 30 patients. Patient age range was 16-74 years (median 50); 18 of 30 patients were female. Eight tumors arose in the lower and two in the upper extremities, seven on the trunk, five each in the head/ neck and anogenital regions, two in the mediastinum, and one in the abdomen. Seventeen neoplasms were located in deep soft tissues, nine were subcutaneous or perifascial, and four were dermal; size ranged from 0.4 to 10 cm; in 11 cases the tumor was > 5 cm.
Tumors with an infiltrative growth pattern were more common than entirely circumscribed lesions. The tumors were composed histologically of short strands, cords, or small clusters of epithelioid, round, to slightly spindled endothelial cells that formed at least focally, intracellular lumina and were set in a frequently myxohyaline stroma. Thirteen of 30 lesions showed angiocentric growth, which was occlusive in many cases. Immunohistochemically, all cases tested were positive for at least one endothelial marker (CD31, CD34, factor VIII, Ulex europaeus), six of 23 (26%) were positive for cytokeratin, and five of 11 (45%) were positive for alpha-smooth muscle actin. Median follow-up of 36 months (range 2-96) in 24 cases showed local recurrence in three cases and systemic metastases in five cases (21%); four patients (17%) died of tumor.
Although more aggressive histologic features (striking nuclear atypia in eight cases, numerous spindled cells in 10, more than two mitoses per 10 high-power fields in nine, and small, more solid angiosarcomalike foci in four cases) tended to be related to poor clinical outcome, there was no clear correlation. Two metastasizing cases showed no histologically atypical features whatever.
We suggest that EHE of soft tissue is better regarded as a fully malignant, rather than borderline, vascular neoplasm, albeit the prognosis is better than in conventional angiosarcoma.
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