VIEWS AND REVIEWS IN VASCULAR MEDICINE AND BIOLOGY
Angiodysplasia: New Look at an Old Conundrum J. T. Lie, MD Department of Pathology, University of California Davis Medical Center, Sacramento, California
11 Angiodysplasia is a unifying concept and designation for all developmental vascular anomalies currently known in the medical literature as angiomatosis, arteriovenous malformation, congenital arteriovenous fistula, congenital hemangioma or lymphangiomatosis, telangiectasia, vascular hamartoma, and all those clinical disorders identified by eponyms, such as Klippel-Tranaunay syndrome and Rendu-Osler-Weber syndrome. A new classification is proposed to catalog the histomorphologic spectrum of angiodysplasia likely to be found in each individual case with the caveat that virtually all angiodysplastic lesions will have mixed histomorphology although one type may predominate. Examples of the most commonly encountered angiodysplastic lesions are described and illustrated in this review. Cardiovasc Pathol 1997;6:247–259 © 1997 by Elsevier Science Inc.
Angiodysplasia is a generic term denoting departure from normal of the arteries, veins, capillaries, and/or lymph vessels, ab initio, with alteration in the size, shape, organization, and configuration of the vascular walls and channels. Angiodysplasia is therefore an all embracing term for such sundry designations of developmental vascular abnormalities that one finds in the current medical literature: angiomatosis, arteriovenous malformation, congenital arteriovenous fistula, congenital hemangioma, congenital vascular defect, lymphangiomatosis, telangiectasia, vascular anomaly, vascular hamartoma, and vascular malformation; as well as all those specific syndromes known by their eponyms, such as Gorham syndrome, Klippel-Trenaunay syndrome, RenduOsler-Weber syndrome (hereditary hemorrhagic telangiectasia), Servelle-Martorell syndrome, Sturge-Weber-Krabbe syndrome, and Von Hippel-Lindau syndrome (1–11). Angiodysplasia is a disease of antiquity of unknown etiology. As early as 1852, Carl Rokitansky apparently observed telangiectatic lesions (hemangiomas) in the mucous membrane of the intestine, and he asserted that although hemangiomas are capable of development after birth, they are usually of congenital origin. Rokitansky believed that the
hemangiomas represented simple hypertrophy of the vascular segments without neoplastic overgrowth (12). Angiodysplasia is an aberration in vascular histogenesis but not an inherited condition and, therefore, Galdabini first introduced the term in 1974 by substituting for the Latin roots of “vascular malformation” their Greek equivalent to avoid the connotation of a congenital origin (13). Angiodysplasia may occur in virtually any part of the human body within the systemic, pulmonary, or cerebral circulation; and in the viscera, soft tissues, or bones. Angiodysplasia is an old clinicopathological conundrum because of the confusing terminology in use, fueled by an abundance of disparate classifications of limited application and acceptance. This article presents a new look at a practical classification and a review of the histopathology of angiodysplasia.
Classifications of Angiodysplasia, Old and New
Manuscript received January 10, 1997; accepted March 12, 1997. Address for correspondence: J. T. Lie, MD, Department of Pathology, UC Davis Medical Center, 2315 Stockton Boulevard, Sacramento, CA 95817. (Reprints not available.)
In the English-language literature alone, several major monographs have been written on the various aspects of angiodysplasia (14–17); and there have also been numerous attempts to classify angiodysplasia (18–24) but none is satisfactory or universally accepted. Most of the suggested classification schemes employ a plethora of terminology with tacit assumption of embryogenesis, resulting in more confusion than clarification. Some proposed classifications are over simplified (20,22) or restricted to angiodysplasia of
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Table 1. 1988 Hamburg Classification of Congenital Vascular Malformations Species Predominantly arterial defects Predominantly venous defects Predominantly A-V shunting defects Combined vascular defects
Truncular Forms
Extratruncular Forms
Aplasia, obstruction, or dilatation Aplasia, obstruction, or dilatation Deep or superficial shunting defects Arterial, venous, and angiolymphatic
Infiltrating or limited Infiltrating or limited Infiltrating or limited Infiltrating or limited
the limbs (18,19); others are too diffuse and complex (15,23,24)—Malan named 20 subtypes (15), Leu included coarctation and arteriomegaly (23), and the most recently proposed classification by Bartels and Horsch (24) listed no fewer than eight separate tables of subclassification. The Hamburg Classification of vascular malformations (Table 1) is a consensus document of a 1988 International Workshop held in Germany and attended by predominantly European participants (22). This classification has the advantages of simplicity and the inclusion of arteriovenous shunting as one of the classification criteria. An important clinical distinction to be made among different types of angiodysplasia is the presence or absence of arteriovenous shunting; the magnitude of shunting in individual lesions
may range from inconsequential to massive and hemodynamically compromising. The Hamburg Classification, however, has some glaring deficiencies. First, artierovenous shuntings in angiodysplasia are essentially a clinicoangiographic and hemodynamic determination, and not a reliable pathologic diagnosis because such shuntings can seldom be demonstrated histologically (7). Second, hemangiomatosis and lymphangiomatosis, both common forms of angiodysplasia have not been included. Third, the classification fails to emphasize the frequent occurrence of dysplastic blood vessels which are neither arteries nor veins histologically (Figure 1). A more desirable new classification of angiodysplasia should be without these deficiencies, if possible; remains simple and yet is still all inclusive, applicable for all ana-
Figure 1. Matching hematoxylin-eosin (A) and elastic stain (B) sections of dysplastic blood vessels that are neither arteries nor veins with absence of elastica in the vessel walls. (Magnification, 3160.)
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Table 2. Proposed New Classification of Angiodysplasia Histologic Categories Hemangiomatosis, capillary or cavernous Lymphangiomatosis (dysplastic lymphatics) Mixed hemangiomatosis and lymphangiomatosis Predominantly arterial angiodysplasia Predominantly venous angiodysplasia Mixed arteriovenous (A-V) angiodysplasia; with or without angiomatous components Specific eponymic syndromes (e.g., Rendu-Osler-Weber syndrome, Klippel-Trenaunay syndrome)
tomical locations of the body human (Table 2). It must be clearly pointed out, however, that the proposed new classification is meant to catalog the spectrum of histomorphological variants that one may find in virtually all angiodysplastic lesions irrespective of their anatomical sites. The predominant morphologic types and their admixture remain highly variable within any single lesion. In other words, there is not a stereotypic histomorphology of angiodysplasia for any particular site. At issue is the examining pathologist’s abil-
Additional Features Localized or infiltrating Localized or infiltrating Localized or infiltrating With or without angiomatous components With or without angiomatous components With or without demonstrable A-V shunting; localized or infiltrating Usually mixed angiomatosis and venous or arterial angiodysplasia with or without demonstrable arteriovenous shunting
ity to distinguish structurally normal arteries/arterioles or veins/venules, and their dysplastic or hybrid equivalents.
Histopathologic Spectrum of Angiodysplasia The histopathology of angiodysplasia in any given location of the body can be quite variable from one area to the next even only a few centimeters apart and, therefore, systematic sampling at multiple sites is a prerequisite for an ad-
Figure 2. An unrecognizable mass (?) in hematoxylin-eosin section (A) infiltrating muscle (M) and fat (F) is shown clearly to be a dysplastic vein (DV) in elastic stain section (B). (Magnification, 3160.)
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Figure 3. A tangled mass of blood vessels infiltrating muscle (M) and fibroadipose tissue (F) in H&E section (A) are dysplastic arteries (A) and veins (V) in elastic stain section (B). (Magnification, 364.)
equate and complete evaluation of the whole specimen. It is essential that matching hematoxylin-eosin and elastic stain sections be routinely processed and examined for the recognition of not only the presence of dysplastic blood vessels
(Figure 1) but also whether the dysplastic blood vessels are veins or arteries (Figure 2), or both (Figure 3). Although angiodysplasia is not considered to be neoplastic, the angiomatosis variety is often an infiltrating process intermingling
Figure 4. Anatomic sites of soft tissue angiodysplasia in 185 patients. (Source: (1), with permission.)
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Figure 5. Low (A) and high (B) magnification views of capillary and cavernous hemangioma as a soft tissue angiodysplasia. (Hematoxylin-eosin stains, A 340, B 3400.)
Figure 6. Low (A) and high (B) magnification views of capillary and cavernous hemangioma as a soft tissue angiodysplasia infiltrating muscle (M). (Hematoxylin-eosin stains, A 316, B 3160.)
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Figure 7. Low (A) and high (B) magnification views of an endovascular hemangioma enclosed in dysplastic vein (DV) as a soft tissue angiodysplasia. (Hematoxylin-eosin stains, A 316, B 3400.)
with the adjacent skeletal muscle fibers and adipocytes without a clearcut delineating margin (Figures 2 and 3); it can certainly recur if the lesion is incompletely excised.
Soft Tissue and Musculoskeletal Angiodysplasia Angiodysplasia occurs most commonly in the soft tissue of lower and upper extremities, including the pelvic girdle and shoulder girdle, respectively. A 50-year (1931–1980) retrospective review of medical records at the Mayo Clinic identified 185 cases of subcutaneous and soft tissue “congenital arteriovenous malformations” (25). There were 100 female and 85 male patients in the total group. The mean age at which patients first became aware of a lesion was 8.3 (median, 1.9) years; the mean age at symptom onset was 15.1 (median, 11.0) years; the mean age at diagnosis was 21.0 (median, 18.5) years; the mean follow-up period after the first Mayo Clinic visit was 11.5 (maximum, 49.8) years; and of the three (1.6% of total) who died of their disease, two died from congestive heart failure and one died of surgical complications. Lesion distribution by anatomic sites in the 185 patients is shown in Figure 4; the lower extremity lesions predominated over those of the upper extremity by a ratio of 3:2.
Specimens from 135 (73%) of these 185 patients and from a more recently reported group of all 36 patients with facial vascular anomalies (8), a grand total of 171, were available for histological review. All six categories of the vascular lesions listed in Table 2 may be seen in subcutaneous and soft tissue angiodysplasia; they are often mixed but one category may occasionally predominate. The most frequently encountered categories are hemangiomas or lymphangiomas combined with venous angiodysplasia, followed by venous angiodysplasia; and the least common are isolated arterial angiodysplasia and mixed arteriovenous angiodysplasia with histologically demonstrable direct arteriovenous communication, or shunting. Capillary and cavernous hemangiomas frequently coexist, distinguishable by the different caliber of the vascular channels they form, with an interstitium consisting of irregular nests of endothelial cells devoid of lumens and interlacing collagen fibers (Figure 5). These hemangiomas may appear fairly well circumscribed but, on closer examination, they are often observed to be infiltrating and thereby separating the adjacent skeletal muscle fibers (Figure 6). An endovascular hemangioma enclosed within the lumen of a dysplastic vein needs to be distinguished from an organized thrombus (Figure 7). When a hemangioma coexists with
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Figure 8. (A) Sclerosing capillary hemangioma infiltrating muscle (M). (Hematoxylin-eosin stains, 3160.) Coexisting with (B) sclerosing dysplastic vein (SDV). (Elastic stain, 340.)
Figure 9. (A) Mixed venous hemangioma and lymphangioma, and (B) isolated lymphangioma in soft tissue angiodysplasia. (Hematoxylin-eosin stains, A 364, B 3160.)
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venous angiodysplasia, both may show their infiltrating propensity and sclerosing involutional changes (Figure 8). Lymphangiomas are recognized by the histological pattern of irregular and often elongated, thin-walled channels lined by flattened endothelial cells with a flimsy external smooth muscle coat and lumens that usually appear empty but may contain a thin film of proteinaceous fluid and the occasional “floater” erythrocytes. Lymphangiomas may be isolated but more often they coexist with hemangiomas or venous dysplasia (Figure 9). A complete evaluation of mixed arteriovenous angiodysplasia most definitely needs elastic stain preparations for the identification of dysplastic arteries and veins (Figures 3 and 10), and may also require serial or step sections to trace out and document the elusive direct arteriovenous shunting (Figure 10). Histological demonstration of large-vessel arteriovenous shunting is difficult and that of small vessels with calibers less than 1 mm in diameter is virtually impossible.
Visceral Angiodysplasia Any discussion of visceral angiodysplasia is by necessity a discussion of gastrointestinal angiodysplasia because of
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its extraordinarily frequent occurrence in the digestive tract relative to other viscera. Its true incidence and prevalence are unknown because many patients with the lesions remain asymptomatic; radiological literature indicates that in various reported series when angiography has been used to evaluate patients with intestinal bleeding, vascular malformations have been incriminated in 12% to 70% of the cases (26). Of note, gastrointestinal angiodysplasia as a final anatomic diagnosis appeared on at least four occasions in the last 5 years among the clinicopathologic conferences published in the venerable New England Journal of Medicine (27–30). A classification of gastrointestinal angiodysplasia based on clinicopathological criteria, as proposed by Camilleri et al. (31), may be reconstructed to include the following five types. The first is arteriovenous malformation with predominantly thick- and thin-walled dysplastic veins. The second is hereditary hemorrhagic telangiectasia or Rendu-OslerWeber syndrome (11). The third includes hamartomatous vascular lesions found in the Peutz-Jeghers, blue rubber bleb nevus and Klippel-Trenaunay syndromes (7). The fourth refers to gastrointestinal (usually right-sided colonic)
Figure 10. Arteriovenous malformations formed by separate or conjoined dysplastic arteries (DA) and dysplastic veins (DV) with multifocal (A) and unifocal (B) arteriovenous shuntings (arrows). (Elastic stain, 364.)
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angiodysplasia associated with aortic valve stenosis, the socalled Hyde syndrome (32). The fifth is massive gastrointestinal bleeding caused by localized, submucosal large-vessel lesions, the so-called Dieulafoy’s malformation (27,28,30, 33,34). Only the first and fifth types, the usual and unusual varieties, respectively, of gastrointestinal angiodysplasia will be highlighted here. Gross indentification of vascular anomalies for tissue sample selections in a surgical specimen can be difficult if not impossible without an intravascular injection technique. Thelmo et al. (35), however, described a relatively simple method of first applying intraluminal fixation with formalin for 3 hours, followed by dissection of the mucosa from the muscle layer, thereby allowing visualization of the vascular lesions by transillumination. Some gastrointestinal angiodysplasia can be notoriously difficult to recognize without a prior vessel-injection technique while others can be quite readily identified by light microscopy at scanning magnification in an elastic-stain section, even without having first treated the gross specimen by the Thelmo technique (35). They appear as multiple di-
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lated and tortuous blood vessels located primarily in the submucosa but may focally penetrate into the mucosa, reaching the luminal surface, or buried deep in the muscularis layer of the bowel wall. These abnormal blood vessels are predominantly dysplastic veins with exceedingly thick or thin walls, the latter variety may also be so dilated as to have a pleated or infolding wall circumference (Figure 11). Dieulafoy’s vascular malformation (also known as Dieulafoy’s disease, Dieulafoy’s lesion, Dieulafoy’s erosion, and Dieulafoy’s ulcer) is a peculiar, usually solitary, submucosal, large-vessel venous angiodysplasia that causes massive gastrointestinal hemorrhage wherever it is located. It is not “caliber-persistent artery of the stomach,” “cirsoid aneurysm,” or “submucosal arterial malformation” of the gastrointestinal tract (27,28). Dieulafoy’s vascular malformation was originally described in the stomach of two patients by Gallard in 1884 (36), but now in the literature it is named after Dieulafoy, a French surgeon who published several case reports of the same gastric lesion 13 years later (37). The angiodysplasia probably still occurs most commonly in the stomach, with about 140 cases reported in the literature
Figure 11. (A) Low magnification view of intestinal angiodysplasia with thick-walled (open arrows) and dilated thin-walled (closed arrows) submucosal dysplastic veins. (B) Close-up view of two dilated thin-walled dysplastic veins, one of which has infolding vessel wall. (Hematoxylin-eosin stains, A 340, B 3160.)
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(28,34), but it has also been found in the jejunum (27), and colon (33). Dieulafoy’s malformation is distinctive histopathologically. A large-caliber, thick-walled, and usually solitary dysplastic vein is found in the submucosa and it may be associated with mucosal ulceration. However, the overlying ulcer lacks the intense inflammation typical of peptic disease and is superficial, with no involvement of the muscularis propria or associated mural fibrosis (38). Histologically, the dysplastic vein may show vessel wall smooth muscle fiber disarray and, rarely, endovascular adipocyte metaplasia (Figure 12).
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langiectasia (40–42) and, most recently, “malalignmant of lung vessels and alveolar capillary dysplasia” (43). To date, at least 500 to 600 cases of pulmonary angiodysplasia have been recorded in the literature. Because arteriovenous shunting may be hemodynamically compromising to the patients, clinical interest in pulmonary angiodysplasia focuses mainly on its diagnosis and treatment surgically or by interventional radiology (40,42). The histopathologic variants that may be observed in surgically resected specimens include large-vessel angiodysplasia, with or without demonstrable arteriovenous shunting, and capillary or cavernous hemangioma (Figure 13).
Central Nervous System Angiodysplasia Pulmonary Angiodysplasia As is with angiodysplasia elsewhere in the body, pulmonary angiodysplasia has a confusing array of synonyms; the condition was originally described by Churton as “multiple aneurysms” in 1897 (39) and subsequently it has become known as pulmonary arteriovenous malformation, pulmonary arteriovenous fistula, pulmonary varix, pulmonary te-
Vascular malformations of the brain are broadly classified into four categories: they are, in descending order of incidence, arteriovenous malformations, cavernous malformations, venous malformations, and the telangiectasias. This generally accepted nomenclature derives from the differences in histopathological characteristics (Figure 14) and in their appearances on angiograms, computed tomography,
Figure 12. (A) Low magnification view of a colonic Dieulafoy’s malformation with a solitary large submucosal dysplastic vein (DV) with close-up views of (B) vessel wall smooth muscle fiber disarray and (C) endovascular adipocyte metaplasia. (Hematoxylin-eosin stains, A 340, B and C 3160.)
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and magnetic resonance imaging (44). The usual clinical course varies with each type, as must plans for management. Cerebral angiodysplasia accounts for roughly 1% of acute strokes; morbidity and mortality of angiodysplasia of the brain result from massive subarachnoid or intracerebral hemorrhage, with a yearly risk of first hemorrhage ranging from 1% to 4% and yearly rebleeding rates as high as 3% (45). In contrast, compression by tortuous elongation of the intramedullary vessels is the apparent cause of the parenchymal softening in spinal cord and angiodysplasia (46).
Conclusion Because of the existing confusing terminology, lack of a universally accepted classification, and uncertainties in its histogenesis and natural history, angiodysplasia (vascular malformations) is a nosologic quagmire that most pathologists fear to tread. Enzinger and Weiss have expressed their opinion of hemangiomas and vascular malformations in this way (47): “We have made no attempt to rigorously separate hemangiomas and malformations from benign neoplasms
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and have for purposes of discussion considered most benign vascular lesions encountered by the surgical pathologist as hemangiomas.” The surgical pathologist’s view on angiodysplasia may be similar to that of the dermatopathologist’s view on cutaneous lymphocytic vasculitis (48). To paraphrase the dermatopathologist, substituting “cutaneous lymphocytic vasculitis” with “angiodysplasia,” one might say that the subject of angiodysplasia has been like a deranged relative left abandoned in the attic of surgical pathology, who, from time to time, will resurface in unpredictable guises that can bewilder any study of the subject. After a fresh new look, however, one may concede that angiodysplasia to the general surgical pathologists, far from being a barren subject, is ripe for further exploration. With precise definitions, a practical classification, and careful histological observation, the general surgical pathologist can make considerable headway in the heretofore bewildering area of angiodysplasia. The proposed new classification catalogs the spectrum of histomorphologic variants that one may find in virtually all angiodysplastic lesions irrespective of their anatomical sites. Conversely, no angiodysplastic lesion anywhere should be expected to be represented by a
Figure 13. (A) Pulmonary angiodysplasia with predominantly small and large dysplastic veins (DV) and no demonstrable arteriovenous shunting. (Elastic stain, 364.) (B) Cavernous hemangioma as pulmonary angiodysplasia. (Hematoxylin-eosin stain, 340.)
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Figure 14. (A) Arteriovenous malformation of the brain with thick-walled dysplastic artery (DA) and part of a thin-walled dysplastic vein (DV, arrow), shown in its entirety close-up in (B) (Elastic stain, A 316, B 364.)
single histomorphologic type in the proposed new classification.
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Angiodysplasia: New Look at an Old Conundrum J. T. Lie, MD Department of Pathology, University of California Davis Medical Center, Sacramento, California
11 Angiodysplasia is a unifying concept and designation for all developmental vascular anomalies currently known in the medical literature as angiomatosis, arteriovenous malformation, congenital arteriovenous fistula, congenital hemangioma or lymphangiomatosis, telangiectasia, vascular hamartoma, and all those clinical disorders identified by eponyms, such as Klippel-Tranaunay syndrome and Rendu-Osler-Weber syndrome. A new classification is proposed to catalog the histomorphologic spectrum of angiodysplasia likely to be found in each individual case with the caveat that virtually all angiodysplastic lesions will have mixed histomorphology although one type may predominate. Examples of the most commonly encountered angiodysplastic lesions are described and illustrated in this review. Cardiovasc Pathol 1997;6:247–259 © 1997 by Elsevier Science Inc.
Angiodysplasia is a generic term denoting departure from normal of the arteries, veins, capillaries, and/or lymph vessels, ab initio, with alteration in the size, shape, organization, and configuration of the vascular walls and channels. Angiodysplasia is therefore an all embracing term for such sundry designations of developmental vascular abnormalities that one finds in the current medical literature: angiomatosis, arteriovenous malformation, congenital arteriovenous fistula, congenital hemangioma, congenital vascular defect, lymphangiomatosis, telangiectasia, vascular anomaly, vascular hamartoma, and vascular malformation; as well as all those specific syndromes known by their eponyms, such as Gorham syndrome, Klippel-Trenaunay syndrome, RenduOsler-Weber syndrome (hereditary hemorrhagic telangiectasia), Servelle-Martorell syndrome, Sturge-Weber-Krabbe syndrome, and Von Hippel-Lindau syndrome (1–11). Angiodysplasia is a disease of antiquity of unknown etiology. As early as 1852, Carl Rokitansky apparently observed telangiectatic lesions (hemangiomas) in the mucous membrane of the intestine, and he asserted that although hemangiomas are capable of development after birth, they are usually of congenital origin. Rokitansky believed that the
hemangiomas represented simple hypertrophy of the vascular segments without neoplastic overgrowth (12). Angiodysplasia is an aberration in vascular histogenesis but not an inherited condition and, therefore, Galdabini first introduced the term in 1974 by substituting for the Latin roots of “vascular malformation” their Greek equivalent to avoid the connotation of a congenital origin (13). Angiodysplasia may occur in virtually any part of the human body within the systemic, pulmonary, or cerebral circulation; and in the viscera, soft tissues, or bones. Angiodysplasia is an old clinicopathological conundrum because of the confusing terminology in use, fueled by an abundance of disparate classifications of limited application and acceptance. This article presents a new look at a practical classification and a review of the histopathology of angiodysplasia.
Classifications of Angiodysplasia, Old and New
Manuscript received January 10, 1997; accepted March 12, 1997. Address for correspondence: J. T. Lie, MD, Department of Pathology, UC Davis Medical Center, 2315 Stockton Boulevard, Sacramento, CA 95817. (Reprints not available.)
In the English-language literature alone, several major monographs have been written on the various aspects of angiodysplasia (14–17); and there have also been numerous attempts to classify angiodysplasia (18–24) but none is satisfactory or universally accepted. Most of the suggested classification schemes employ a plethora of terminology with tacit assumption of embryogenesis, resulting in more confusion than clarification. Some proposed classifications are over simplified (20,22) or restricted to angiodysplasia of
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Table 1. 1988 Hamburg Classification of Congenital Vascular Malformations Species Predominantly arterial defects Predominantly venous defects Predominantly A-V shunting defects Combined vascular defects
Truncular Forms
Extratruncular Forms
Aplasia, obstruction, or dilatation Aplasia, obstruction, or dilatation Deep or superficial shunting defects Arterial, venous, and angiolymphatic
Infiltrating or limited Infiltrating or limited Infiltrating or limited Infiltrating or limited
the limbs (18,19); others are too diffuse and complex (15,23,24)—Malan named 20 subtypes (15), Leu included coarctation and arteriomegaly (23), and the most recently proposed classification by Bartels and Horsch (24) listed no fewer than eight separate tables of subclassification. The Hamburg Classification of vascular malformations (Table 1) is a consensus document of a 1988 International Workshop held in Germany and attended by predominantly European participants (22). This classification has the advantages of simplicity and the inclusion of arteriovenous shunting as one of the classification criteria. An important clinical distinction to be made among different types of angiodysplasia is the presence or absence of arteriovenous shunting; the magnitude of shunting in individual lesions
may range from inconsequential to massive and hemodynamically compromising. The Hamburg Classification, however, has some glaring deficiencies. First, artierovenous shuntings in angiodysplasia are essentially a clinicoangiographic and hemodynamic determination, and not a reliable pathologic diagnosis because such shuntings can seldom be demonstrated histologically (7). Second, hemangiomatosis and lymphangiomatosis, both common forms of angiodysplasia have not been included. Third, the classification fails to emphasize the frequent occurrence of dysplastic blood vessels which are neither arteries nor veins histologically (Figure 1). A more desirable new classification of angiodysplasia should be without these deficiencies, if possible; remains simple and yet is still all inclusive, applicable for all ana-
Figure 1. Matching hematoxylin-eosin (A) and elastic stain (B) sections of dysplastic blood vessels that are neither arteries nor veins with absence of elastica in the vessel walls. (Magnification, 3160.)
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Table 2. Proposed New Classification of Angiodysplasia Histologic Categories Hemangiomatosis, capillary or cavernous Lymphangiomatosis (dysplastic lymphatics) Mixed hemangiomatosis and lymphangiomatosis Predominantly arterial angiodysplasia Predominantly venous angiodysplasia Mixed arteriovenous (A-V) angiodysplasia; with or without angiomatous components Specific eponymic syndromes (e.g., Rendu-Osler-Weber syndrome, Klippel-Trenaunay syndrome)
tomical locations of the body human (Table 2). It must be clearly pointed out, however, that the proposed new classification is meant to catalog the spectrum of histomorphological variants that one may find in virtually all angiodysplastic lesions irrespective of their anatomical sites. The predominant morphologic types and their admixture remain highly variable within any single lesion. In other words, there is not a stereotypic histomorphology of angiodysplasia for any particular site. At issue is the examining pathologist’s abil-
Additional Features Localized or infiltrating Localized or infiltrating Localized or infiltrating With or without angiomatous components With or without angiomatous components With or without demonstrable A-V shunting; localized or infiltrating Usually mixed angiomatosis and venous or arterial angiodysplasia with or without demonstrable arteriovenous shunting
ity to distinguish structurally normal arteries/arterioles or veins/venules, and their dysplastic or hybrid equivalents.
Histopathologic Spectrum of Angiodysplasia The histopathology of angiodysplasia in any given location of the body can be quite variable from one area to the next even only a few centimeters apart and, therefore, systematic sampling at multiple sites is a prerequisite for an ad-
Figure 2. An unrecognizable mass (?) in hematoxylin-eosin section (A) infiltrating muscle (M) and fat (F) is shown clearly to be a dysplastic vein (DV) in elastic stain section (B). (Magnification, 3160.)
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Figure 3. A tangled mass of blood vessels infiltrating muscle (M) and fibroadipose tissue (F) in H&E section (A) are dysplastic arteries (A) and veins (V) in elastic stain section (B). (Magnification, 364.)
equate and complete evaluation of the whole specimen. It is essential that matching hematoxylin-eosin and elastic stain sections be routinely processed and examined for the recognition of not only the presence of dysplastic blood vessels
(Figure 1) but also whether the dysplastic blood vessels are veins or arteries (Figure 2), or both (Figure 3). Although angiodysplasia is not considered to be neoplastic, the angiomatosis variety is often an infiltrating process intermingling
Figure 4. Anatomic sites of soft tissue angiodysplasia in 185 patients. (Source: (1), with permission.)
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Figure 5. Low (A) and high (B) magnification views of capillary and cavernous hemangioma as a soft tissue angiodysplasia. (Hematoxylin-eosin stains, A 340, B 3400.)
Figure 6. Low (A) and high (B) magnification views of capillary and cavernous hemangioma as a soft tissue angiodysplasia infiltrating muscle (M). (Hematoxylin-eosin stains, A 316, B 3160.)
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Figure 7. Low (A) and high (B) magnification views of an endovascular hemangioma enclosed in dysplastic vein (DV) as a soft tissue angiodysplasia. (Hematoxylin-eosin stains, A 316, B 3400.)
with the adjacent skeletal muscle fibers and adipocytes without a clearcut delineating margin (Figures 2 and 3); it can certainly recur if the lesion is incompletely excised.
Soft Tissue and Musculoskeletal Angiodysplasia Angiodysplasia occurs most commonly in the soft tissue of lower and upper extremities, including the pelvic girdle and shoulder girdle, respectively. A 50-year (1931–1980) retrospective review of medical records at the Mayo Clinic identified 185 cases of subcutaneous and soft tissue “congenital arteriovenous malformations” (25). There were 100 female and 85 male patients in the total group. The mean age at which patients first became aware of a lesion was 8.3 (median, 1.9) years; the mean age at symptom onset was 15.1 (median, 11.0) years; the mean age at diagnosis was 21.0 (median, 18.5) years; the mean follow-up period after the first Mayo Clinic visit was 11.5 (maximum, 49.8) years; and of the three (1.6% of total) who died of their disease, two died from congestive heart failure and one died of surgical complications. Lesion distribution by anatomic sites in the 185 patients is shown in Figure 4; the lower extremity lesions predominated over those of the upper extremity by a ratio of 3:2.
Specimens from 135 (73%) of these 185 patients and from a more recently reported group of all 36 patients with facial vascular anomalies (8), a grand total of 171, were available for histological review. All six categories of the vascular lesions listed in Table 2 may be seen in subcutaneous and soft tissue angiodysplasia; they are often mixed but one category may occasionally predominate. The most frequently encountered categories are hemangiomas or lymphangiomas combined with venous angiodysplasia, followed by venous angiodysplasia; and the least common are isolated arterial angiodysplasia and mixed arteriovenous angiodysplasia with histologically demonstrable direct arteriovenous communication, or shunting. Capillary and cavernous hemangiomas frequently coexist, distinguishable by the different caliber of the vascular channels they form, with an interstitium consisting of irregular nests of endothelial cells devoid of lumens and interlacing collagen fibers (Figure 5). These hemangiomas may appear fairly well circumscribed but, on closer examination, they are often observed to be infiltrating and thereby separating the adjacent skeletal muscle fibers (Figure 6). An endovascular hemangioma enclosed within the lumen of a dysplastic vein needs to be distinguished from an organized thrombus (Figure 7). When a hemangioma coexists with
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Figure 8. (A) Sclerosing capillary hemangioma infiltrating muscle (M). (Hematoxylin-eosin stains, 3160.) Coexisting with (B) sclerosing dysplastic vein (SDV). (Elastic stain, 340.)
Figure 9. (A) Mixed venous hemangioma and lymphangioma, and (B) isolated lymphangioma in soft tissue angiodysplasia. (Hematoxylin-eosin stains, A 364, B 3160.)
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venous angiodysplasia, both may show their infiltrating propensity and sclerosing involutional changes (Figure 8). Lymphangiomas are recognized by the histological pattern of irregular and often elongated, thin-walled channels lined by flattened endothelial cells with a flimsy external smooth muscle coat and lumens that usually appear empty but may contain a thin film of proteinaceous fluid and the occasional “floater” erythrocytes. Lymphangiomas may be isolated but more often they coexist with hemangiomas or venous dysplasia (Figure 9). A complete evaluation of mixed arteriovenous angiodysplasia most definitely needs elastic stain preparations for the identification of dysplastic arteries and veins (Figures 3 and 10), and may also require serial or step sections to trace out and document the elusive direct arteriovenous shunting (Figure 10). Histological demonstration of large-vessel arteriovenous shunting is difficult and that of small vessels with calibers less than 1 mm in diameter is virtually impossible.
Visceral Angiodysplasia Any discussion of visceral angiodysplasia is by necessity a discussion of gastrointestinal angiodysplasia because of
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its extraordinarily frequent occurrence in the digestive tract relative to other viscera. Its true incidence and prevalence are unknown because many patients with the lesions remain asymptomatic; radiological literature indicates that in various reported series when angiography has been used to evaluate patients with intestinal bleeding, vascular malformations have been incriminated in 12% to 70% of the cases (26). Of note, gastrointestinal angiodysplasia as a final anatomic diagnosis appeared on at least four occasions in the last 5 years among the clinicopathologic conferences published in the venerable New England Journal of Medicine (27–30). A classification of gastrointestinal angiodysplasia based on clinicopathological criteria, as proposed by Camilleri et al. (31), may be reconstructed to include the following five types. The first is arteriovenous malformation with predominantly thick- and thin-walled dysplastic veins. The second is hereditary hemorrhagic telangiectasia or Rendu-OslerWeber syndrome (11). The third includes hamartomatous vascular lesions found in the Peutz-Jeghers, blue rubber bleb nevus and Klippel-Trenaunay syndromes (7). The fourth refers to gastrointestinal (usually right-sided colonic)
Figure 10. Arteriovenous malformations formed by separate or conjoined dysplastic arteries (DA) and dysplastic veins (DV) with multifocal (A) and unifocal (B) arteriovenous shuntings (arrows). (Elastic stain, 364.)
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angiodysplasia associated with aortic valve stenosis, the socalled Hyde syndrome (32). The fifth is massive gastrointestinal bleeding caused by localized, submucosal large-vessel lesions, the so-called Dieulafoy’s malformation (27,28,30, 33,34). Only the first and fifth types, the usual and unusual varieties, respectively, of gastrointestinal angiodysplasia will be highlighted here. Gross indentification of vascular anomalies for tissue sample selections in a surgical specimen can be difficult if not impossible without an intravascular injection technique. Thelmo et al. (35), however, described a relatively simple method of first applying intraluminal fixation with formalin for 3 hours, followed by dissection of the mucosa from the muscle layer, thereby allowing visualization of the vascular lesions by transillumination. Some gastrointestinal angiodysplasia can be notoriously difficult to recognize without a prior vessel-injection technique while others can be quite readily identified by light microscopy at scanning magnification in an elastic-stain section, even without having first treated the gross specimen by the Thelmo technique (35). They appear as multiple di-
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lated and tortuous blood vessels located primarily in the submucosa but may focally penetrate into the mucosa, reaching the luminal surface, or buried deep in the muscularis layer of the bowel wall. These abnormal blood vessels are predominantly dysplastic veins with exceedingly thick or thin walls, the latter variety may also be so dilated as to have a pleated or infolding wall circumference (Figure 11). Dieulafoy’s vascular malformation (also known as Dieulafoy’s disease, Dieulafoy’s lesion, Dieulafoy’s erosion, and Dieulafoy’s ulcer) is a peculiar, usually solitary, submucosal, large-vessel venous angiodysplasia that causes massive gastrointestinal hemorrhage wherever it is located. It is not “caliber-persistent artery of the stomach,” “cirsoid aneurysm,” or “submucosal arterial malformation” of the gastrointestinal tract (27,28). Dieulafoy’s vascular malformation was originally described in the stomach of two patients by Gallard in 1884 (36), but now in the literature it is named after Dieulafoy, a French surgeon who published several case reports of the same gastric lesion 13 years later (37). The angiodysplasia probably still occurs most commonly in the stomach, with about 140 cases reported in the literature
Figure 11. (A) Low magnification view of intestinal angiodysplasia with thick-walled (open arrows) and dilated thin-walled (closed arrows) submucosal dysplastic veins. (B) Close-up view of two dilated thin-walled dysplastic veins, one of which has infolding vessel wall. (Hematoxylin-eosin stains, A 340, B 3160.)
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(28,34), but it has also been found in the jejunum (27), and colon (33). Dieulafoy’s malformation is distinctive histopathologically. A large-caliber, thick-walled, and usually solitary dysplastic vein is found in the submucosa and it may be associated with mucosal ulceration. However, the overlying ulcer lacks the intense inflammation typical of peptic disease and is superficial, with no involvement of the muscularis propria or associated mural fibrosis (38). Histologically, the dysplastic vein may show vessel wall smooth muscle fiber disarray and, rarely, endovascular adipocyte metaplasia (Figure 12).
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langiectasia (40–42) and, most recently, “malalignmant of lung vessels and alveolar capillary dysplasia” (43). To date, at least 500 to 600 cases of pulmonary angiodysplasia have been recorded in the literature. Because arteriovenous shunting may be hemodynamically compromising to the patients, clinical interest in pulmonary angiodysplasia focuses mainly on its diagnosis and treatment surgically or by interventional radiology (40,42). The histopathologic variants that may be observed in surgically resected specimens include large-vessel angiodysplasia, with or without demonstrable arteriovenous shunting, and capillary or cavernous hemangioma (Figure 13).
Central Nervous System Angiodysplasia Pulmonary Angiodysplasia As is with angiodysplasia elsewhere in the body, pulmonary angiodysplasia has a confusing array of synonyms; the condition was originally described by Churton as “multiple aneurysms” in 1897 (39) and subsequently it has become known as pulmonary arteriovenous malformation, pulmonary arteriovenous fistula, pulmonary varix, pulmonary te-
Vascular malformations of the brain are broadly classified into four categories: they are, in descending order of incidence, arteriovenous malformations, cavernous malformations, venous malformations, and the telangiectasias. This generally accepted nomenclature derives from the differences in histopathological characteristics (Figure 14) and in their appearances on angiograms, computed tomography,
Figure 12. (A) Low magnification view of a colonic Dieulafoy’s malformation with a solitary large submucosal dysplastic vein (DV) with close-up views of (B) vessel wall smooth muscle fiber disarray and (C) endovascular adipocyte metaplasia. (Hematoxylin-eosin stains, A 340, B and C 3160.)
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and magnetic resonance imaging (44). The usual clinical course varies with each type, as must plans for management. Cerebral angiodysplasia accounts for roughly 1% of acute strokes; morbidity and mortality of angiodysplasia of the brain result from massive subarachnoid or intracerebral hemorrhage, with a yearly risk of first hemorrhage ranging from 1% to 4% and yearly rebleeding rates as high as 3% (45). In contrast, compression by tortuous elongation of the intramedullary vessels is the apparent cause of the parenchymal softening in spinal cord and angiodysplasia (46).
Conclusion Because of the existing confusing terminology, lack of a universally accepted classification, and uncertainties in its histogenesis and natural history, angiodysplasia (vascular malformations) is a nosologic quagmire that most pathologists fear to tread. Enzinger and Weiss have expressed their opinion of hemangiomas and vascular malformations in this way (47): “We have made no attempt to rigorously separate hemangiomas and malformations from benign neoplasms
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and have for purposes of discussion considered most benign vascular lesions encountered by the surgical pathologist as hemangiomas.” The surgical pathologist’s view on angiodysplasia may be similar to that of the dermatopathologist’s view on cutaneous lymphocytic vasculitis (48). To paraphrase the dermatopathologist, substituting “cutaneous lymphocytic vasculitis” with “angiodysplasia,” one might say that the subject of angiodysplasia has been like a deranged relative left abandoned in the attic of surgical pathology, who, from time to time, will resurface in unpredictable guises that can bewilder any study of the subject. After a fresh new look, however, one may concede that angiodysplasia to the general surgical pathologists, far from being a barren subject, is ripe for further exploration. With precise definitions, a practical classification, and careful histological observation, the general surgical pathologist can make considerable headway in the heretofore bewildering area of angiodysplasia. The proposed new classification catalogs the spectrum of histomorphologic variants that one may find in virtually all angiodysplastic lesions irrespective of their anatomical sites. Conversely, no angiodysplastic lesion anywhere should be expected to be represented by a
Figure 13. (A) Pulmonary angiodysplasia with predominantly small and large dysplastic veins (DV) and no demonstrable arteriovenous shunting. (Elastic stain, 364.) (B) Cavernous hemangioma as pulmonary angiodysplasia. (Hematoxylin-eosin stain, 340.)
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Figure 14. (A) Arteriovenous malformation of the brain with thick-walled dysplastic artery (DA) and part of a thin-walled dysplastic vein (DV, arrow), shown in its entirety close-up in (B) (Elastic stain, A 316, B 364.)
single histomorphologic type in the proposed new classification.
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