Felipedia

©R. N. Fuji, K. M. Patton, T. J. Steinbach, F. Y. Schulman, G. A. Bradley, T. T. Brown, E. A. Wilson and B. A. Summers. Feline Systemic Reactive Angioendotheliomatosis: Eight Cases and Literature Review. Vet Pathol 42:608-617 (2005)

Since 1985, an unusual multisystemic vascular disease characterizedby intraluminal endothelial and pericyte proliferation has beendocumented in four cats (cat Nos. 9–12, Table 1): onefrom Australia, two from Switzerland, and one from the UK.^7,29,31To our knowledge, similar cases have not been previously reportedin the United States. We believe that the identification ofonly three additional cases catalogued at Cornell Universitysince 1973 and five submitted in consultation since 1998 atteststo the rarity of this condition.

The term angioendotheliomatosis has been used to describe severalintravascular proliferative disorders in humans. While originallyseparated clinicopathologically into benign and malignant variants,during the past 15 years, it has become clear that angioendotheliomatosisactually represents three distinct diseases.^9,26,36 Antigenicphenotyping by immunohistochemistry and limited karyotypic analysishave shown almost all examples of the fatal and multisystemicmalignant variant to be an intravascular, angiotrophic lymphoma(predominantly of B-cell type).^5,13,30,35 Malignant angioendotheliomatosis was originally thought to be a disseminated intraluminal proliferationof neoplastic endothelial cells (angiosarcoma), but only rare examples of this second neoplasm have been substantiated.²²The third variant is benign and reactive, with lesions limitedto the skin, and represents a proliferation of intravascularendothelial cells admixed with pericytes.²⁰

Feline intravascular proliferative disorders are extremely rare,and they fall into one of two categories: intravascular angiotrophiclymphoma and a variant of reactive angioendotheliomatosis (RAE).A single case of malignant intravascular lymphoma has been reportedin a Siamese cat that affected the vessels of the brain andkidney.¹⁹ The intravascular cells consisted of non-cohesive,pleomorphic, round cells that had the immunohistochemical propertiesof T cells. In contrast, four cases of an unnamed, multisystemic,and fatal disease characterized by plump endothelial cells andfewer pericytes proliferating in the vascular lumina have beendocumented by light and electron microscopy and immunohistochemistryin cats.^7,29,31 We describe eight additional cats with thisrare entity, review the four previously documented cases, andpropose the name "feline systemic reactive angioendotheliomatosis"(FSRA) for this unique disease in cats.

Fig. 1. Kidney; cat No. 1. Periglomerular arteriolar expansion and occlusion by fibrin thrombus and exuberant intravascular spindle cell proliferation (arrow). HE. Bar = 60 µm.
Fig. 2. Cerebellum; cat No. 3. Proliferative focus resembling a renal glomerulus. No corresponding parenchymal haemorrhage or necrosis was observed. HE. Bar = 60 µm.
Fig. 3. Heart; cat No. 5. Prominent enlargement of many arterioles within the myocardium by intravascular proliferation of spindle cells. A few vessels contain fibrin thrombi (arrows). HE. Bar = 120 µm.
Fig. 4. Heart; cat No. 6. Severe, chronic involvement of myocardial vessels with formation of glomeruloid structures and marked perivascular adventitial fibroplasia. HE. Bar = 120 µm.
Fig. 5. Heart; cat No. 5. Positive vWF antigen staining of many intraluminal spindle cells indicates endothelial cell histogenesis. Immunohistochemical staining for vWF antigen. Bar = 60 µm.
Fig. 6. Heart; cat No. 5. Positive SMA staining of arteriolar smooth muscle as well as intraluminal cells (pericytes) admixed with endothelial cells. Immunohistochemical staining for SMA. Bar = 60 µm.

In all cats, the majority of intravascular spindle cells (85–95%)stained positively for vimentin, while the proportion of thesecells positive for vWF antigen ranged from 30 to 85% among cats(Fig. 5). A smaller proportion (5–50%) stained positivelyfor SMA (Fig. 6). These results suggest that the proliferatingcells were a mixture of endothelial cells and pericytes. Inthe most severe lesions, the pericytes often encircled the newlyformed endothelial cell-lined channels in an orderly arrangement.In the heart, where thrombi were often seen in the affectedvessels, vWF antibody stained these platelet-rich thrombi aswell as the exuded perivascular plasma. In cat Nos. 1 and 6, the proliferative adventitial fibroblasts were positive forvimentin and negative for vWF antigen and SMA. Only minimalcollagen deposition was detected by Masson's Trichrome stainingwithin and surrounding the vascular plexus. In cat Nos. 1, 2,and 7, all intravascular cells were negative for cytokeratinsand the leukocyte antigens, CD3, CD79a, CD18, and CD45RA. Noorganisms were seen in cat Nos. 5 and 6 by Modified Steinersilver stain.

Ultrastructural examination of the affected vessels in the spinalcord of cat No. 7 revealed the intraluminal cells to be plump,irregular, and primarily spindle-shaped within a network ofinterlacing basal laminae (Fig. 7). Consistent with an endothelialorigin, they contained small amounts of rough endoplasmic reticulum,few plasmalemmal Weibel-Palade bodies, few mitochondria, andopen-faced nuclei with marginated chromatin. Admixed with theseimmature endothelial cells were scattered smaller spindle cells,made more electron dense by cytoplasmic bundles of microfilamentsand separated from the basal lamina by disorganized depositsof collagen fibrils. Laminated clusters of fibrin, platelets,and occasional erythrocytes were also seen within vascular lumina.No infectious organisms were identified in the lesions.

Fig. 7. Spinal cord; cat No. 7. Electron microscopic examination shows an intravascular mixture of plump endothelial (E) and pericyte-like (P) cells within a network of interlacing basal laminae. Fibrin, platelets, and erythrocytes are also present within the vascular lumen (F). Bar = 1.8 µm.

In the cats ofour study, the lesions varied in both chronicity and severityof the intraluminal proliferation. The majority of involvedvessels appeared to be small arterioles, each composed of athin (1–2 cells thick) tunica media surrounding an endothelialcell–lined lumen and lacking an internal elastic lamina.The location of the affected vessels in the kidney is consistentwith the periglomerular arterioles. Immunostaining for vWF antigenperformed on tissues from the previous cases confirmed thata variable number of the intravascular proliferative spindle cells were of endothelial origin. Immunostaining on the catsof our study was similar. To determine the identity of the remaining vWF-negative spindle cells, Rothwell et al.²⁹ performed electronmicroscopic studies that showed pericyte-like cells admixed with endothelial cells. Our ultrastructural studies yieldedsimilar findings, and the SMA staining of a variable proportionof the proliferative cells in the cats of our study furthersupports a pericytic origin.

No similar multisystemic syndrome has been identified in humans;however, several cutaneous disorders characterized by proliferative,mixed endothelial cell and pericyte, intravascular lesions havebeen described. These include intravascular papillary endothelialhyperplasia (IPEH), RAE, acroangiodermatitis (pseudo-Kaposi'ssarcoma), and glomeruloid hemangioma (POEMS syndrome).²⁸

IPEH was first described by Masson in 1923, named hemangioendotheliomavegetant intravasculaire, and was suspected to be a neoplasm.Now believed to be an unusual form of organizing thrombus, Levereet al.²¹ demonstrated its association with elevations in basicfibroblast growth factor (bFGF). They hypothesized that increasedbFGF results in an autocrine feedback loop, stimulating exuberantendothelial cell proliferation. Clinically, IPEH manifests asa solitary cutaneous nodule that histologically consists ofa dilated blood vessel expanded by numerous papillary ingrowthsof endothelia covering delicate collagenous cores. Ultrastructurally,endothelial cells, pericytes, and undifferentiated cells havebeen identified.⁸ Recently, a case of IPEH has been reportedin the eye of a horse, with the lesion arising from a presumedconjunctival vascular malformation.¹¹ In the feline disorder,the lesions are multisystemic rather than focal and nodular, but the common presence of thrombi within proliferative spindlecell tufts suggests that this lesion also may represent an exaggerated response to thrombosis. In several cats, the distension of the vessels by an intravascular arrangement of small, capillary-sized channels supported by pericytes and interlacing fine collagenfibres is reminiscent of a recanalized vessel.

RAE is the disorder in people that has historically been confusedwith intravascular angiotrophic lymphoma (malignant angioendotheliomatosis),although RAE has always been clinically distinct in that itis confined to the skin and is self-limiting. The cytologicfeatures of RAE differ from lymphoma, with the former characterizedby glomeruloid whorls of bland spindle cells often obliteratingthe lumina of the small dermal vessels and associated with microthrombi.The overlying skin is often erythematous and occasionally ulcerates.The majority of the intravascular cells are immunohistochemicallypositive for vWF antigen, CD34, and Ulex europaeus, indicatingthat they are endothelial. The remainder are positive for muscle-specificactin.^{5,9,20,26,30,35,36} Although the feline vascular lesionsare multisystemic, morphologically and immunohistochemically,they are most similar to this condition in humans. Thus, wepropose the acronym FSRA as the morphologic description of thisdisease.

A variety of associated conditions have been identified in about75% of the approximately 35 reported cases of human RAE.²³ Onehypothesis is that the lesion represents an unusual residuumof leukocytoclastic vasculitis, such as that due to immune complexdeposition in a hypersensitivity reaction. In a 5-month-oldchild studied by Wick and Rocamora,³⁶ the suspected antigenwas a cow's milk protein, as the lesions resolved followingdietary change. Other immune-mediated reactions that have beensuspected to cause this unusual vasculopathy include those associatedwith chronic infections (subacute bacterial endocarditis, Chaga'sdisease, pulmonary tuberculosis, and hepatitis C virus) andautoimmune diseases such as rheumatoid arthritis and systemiclupus erythematosus with anti-phospholipid syndrome.^6,20,26,32In the cats of our study, no underlying infectious or inflammatorydisease was documented clinically or identified at necropsy, and minimal to no inflammatory cells were observed within the affected vessels.

Further cutaneous conditions that may share pathogenic mechanismswith RAE include acroangiodermatitis and glomeruloid hemangioma.Acroangiodermatitis features endothelial cell proliferationassociated with thrombotic vessel recanalization or in responseto the stimulus of endothelial growth factors induced by ischemia,while glomeruloid hemangioma is a rare cutaneous vascular proliferation(resembling renal glomeruli) in humans with POEMS syndrome (Polyneuropathy,Organomegaly, Endocrinopathy, M-protein, Skin changes) and isassociated with multicentric Castleman's disease.^{14,16,27,33,37}

Occlusive, intra-arteriolar endothelial and pericytic proliferations(termed glomera or glomeruloid structures) have also been describedin humans in unusual cases of chronic glomerulonephritis, inplexiform vessels of the lung associated with primary pulmonaryhypertension, and multisystemically in cases of chronic disseminatedintravascular coagulation and thrombotic thrombocytopenic purpura(TTP).³⁴ While the pathogeneses of the vascular lesions aredistinct and complex in these various diseases, all are believedto represent a "unique form of exuberant angiogenesis," witha focus on platelet aggregation, angiogenic cytokines, and/ordysfunctional endothelial regulation of the coagulation andfibrinolytic systems.¹² TTP is characterized by platelet thrombiwithin the small vessels of many organs, primarily the centralnervous system and kidneys. The disease is caused by an inheritedor acquired failure to degrade unusually large multimers ofvWF.^2,25 Although the vascular lesion in cats is histologicallysimilar, the clinical presentation of TTP includes thrombocytopeniaand erythrocyte fragmentation, which were not consistent findingsin the cats of our study.

Proliferative endothelial cell lesions have also been reportedwith infectious diseases in humans with acquired immunodeficiencydue to human immunodeficiency virus, particularly Kaposi's sarcoma(human herpesvirus-8) and bacillary angiomatosis (Bartonellahenselae and Bartonella quintana).^3,4,17 We have viral serologydata on only two animals (cat Nos. 4 and 10), both of whichwere negative for FIV, FeLV, and FIP. A Modified Steiner silverstain was performed on the cardiac tissue from cat Nos. 5 and6, and no organisms suggestive of Bartonella spp. were seen,although PCR may be required to adequately evaluate infectionby these bacteria. Furthermore, our electron microscopic examination,as well as that performed by Rothwell et al.,²⁹ identified noinfectious organisms. In general, infection and bacteremia ofcats with B. henselae (also the cause of human cat scratch fever)have not been associated with any clinical disease; however,in experimental infections, lesions reportedly included lymphnode and splenic lymphoid hyperplasia, cholangitis, hepatitis,nephritis, and myocarditis.^1,10,18 No endothelial proliferativelesions have thus far been seen in cats with experimental Bartonellainfection.

That the bland, mixed intravascular proliferations in thesecats represent an unusual malignant neoplastic condition suchas disseminated intravascular angiosarcoma or endovascular papillaryangioendothelioma (Dabska's tumour) is considered unlikely.²⁶Further, the novel, mixed intravascular lesions of FRSA arereadily distinguished from feline hemangioma and hemangiosarcomaand from the more recently recognized case of cerebral angiomatosis.^15,24

To our knowledge, the vascular lesion reviewed in this studyin cats has not been documented in any other domestic or laboratoryanimal species. The intravascular proliferations are characterizedby glomeruloid whorls of cohesive spindle cells that are immunoreactivefor endothelial cell and pericyte markers. Given the multisystemicnature of this disorder in cats and the morphologic similaritiesto the human entity, RAE, we suggest that this unusual idiopathiclesion be referred to by the acronym FSRA. What remains to bedefined for this condition in these primarily young adult andoften male cats is the underlying disorder (infection? vasculitis?thrombosis?) with a predilection for the myocardial vasculature that precipitates this widespread and fatal disease.