|Year : 2015 | Volume
| Issue : 4 | Page : 139-145
The Adventitial Angioproliferation in Human Immunodeficiency Virus Associated Large Artery Vasculopathy is Not a Manifestation of Kaposi Sarcoma
Balasoobramanien Pillay1, Pratistadevi Kanaye Ramdial2, Amsha Ramburan2, Kievershen Nargan3, Datshana P Naidoo4
1 Department of Vascular/Endovascular Surgery; Nelson R Mandela School of Medicine; University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa
2 Department of Anatomical Pathology; School of Laboratory Medicine and Medical Sciences; University of KwaZulu-Natal; National Health Laboratory Service, Durban, KwaZulu-Natal, South Africa
3 Department of Anatomical Pathology , National Health Laboratory Service, Durban, KwaZulu-Natal, South Africa
4 Department of Cardiology; Nelson R Mandela School of Medicine; University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa
|Date of Web Publication||13-Apr-2016|
Department of Vascular/Endovascular Surgery; Nelson R Mandela School of Medicine; University of KwaZulu-Natal, Durban, KwaZulu-Natal
Source of Support: None, Conflict of Interest: None
Introduction: Human immunodeficiency virus-associated large artery vasculopathy (HIV-vasculopathy) is characterized by distinctive transmural microanatomical alterations, including adventitial angioproliferation, similar to that described in early cutaneous Kaposi sarcoma (KS). Human herpesvirus-8 (HHV8), the etiological agent of KS, is identifiable in tissue sections. The aim of this study was to investigate, based on HHV8-latent nuclear antigen-1 (HHV8-LNA-1) immunohistochemical and HHV8 polymerase chain reaction (PCR) testing, whether KS is the cause of the angioproliferation.
Materials and Methods: Sections from 20 large arteries, ten each with HIV-associated occlusive and aneurysmal vasculopathy and ten biopsies with early cutaneous KS from 30 anti-retroviral therapy naive patients were appraised microscopically and subjected to HHV8-LNA-1 immunostaining. Arterial sections were also subjected to HHV8 PCR investigation with appropriate positive and negative controls.
Results: The microscopic large arterial adventitial alterations included a dissecting proliferation of capillary-caliber vasculature, surrounded by mixed inflammation, microhemorrhages, hemosiderin and vasa vasorum intimomedial fibrosis, and hypertrophy. Ten vessels also demonstrated adventitial leukocytoclastic and lymphocytic vasculitis. Immunohistochemical and PCR detection of HHV8 was consistently negative. Skin biopsies of KS shared the vascular adventitial alterations, but vasculitis and thrombosis were absent. Endothelial and dermal spindle cells were immunopositive for HHV8.
Conclusion: The adventitial angioproliferation in large arteries with HIV-vasculopathy is not a manifestation of KS. The exact roles of HIV, including interaction with co-infective agents and cellular and subcellular responses in the induction of vasculopathic and vasa vasorum abnormalities, including adventitial angioinflammatory alterations, require accelerated investigation for improved disease understanding and patient management.
Keywords: Adventitial, angioproliferation, Human herpesvirus-8, Human immunodeficiency virus-vasculopathy, Kaposi sarcoma
|How to cite this article:|
Pillay B, Ramdial PK, Ramburan A, Nargan K, Naidoo DP. The Adventitial Angioproliferation in Human Immunodeficiency Virus Associated Large Artery Vasculopathy is Not a Manifestation of Kaposi Sarcoma. Indian J Vasc Endovasc Surg 2015;2:139-45
|How to cite this URL:|
Pillay B, Ramdial PK, Ramburan A, Nargan K, Naidoo DP. The Adventitial Angioproliferation in Human Immunodeficiency Virus Associated Large Artery Vasculopathy is Not a Manifestation of Kaposi Sarcoma. Indian J Vasc Endovasc Surg [serial online] 2015 [cited 2019 Dec 12];2:139-45. Available from: http://www.indjvascsurg.org/text.asp?2015/2/4/139/180113
| Introduction|| |
A well-documented relationship between Human immunodeficiency virus (HIV) infection and large, medium, and small blood vessel diseases has emerged in the last two decades. ,,,,, The spectrum of HIV-associated vascular pathology has expanded [Table 1] ,, since the first description in pediatric autopsy studies in 1995,  to include aneurysms,  pseudoaneurysms,  occlusive lesions, , spontaneous arteriovenous fistula,  arterial dissection,  vasculitides and complications of hypercoagulability, and highly active antiretroviral therapy (HAART). , HIV-associated large artery vasculopathy (HIV-vasculopathy) is typified by distinctive histomorphological characteristics [Table 2], ,, but the exact etiopathogenesis of aneurysmal and occlusive large vessel disease is largely unraveled to date.  However, infective and hypersensitivity-related leukocytoclastic vasculitis targeting the vasa vasora of afflicted vessels, with subsequent damage to the vessel wall, has been proposed. ,,, In addition, a peculiar unexplained slit-like adventitial vascular proliferation has been described that shares morphological similarity with early stage Kaposi sarcoma (KS),  a heterogeneous AIDS-defining malignancy. Despite the shared proposed roles of cytokines and growth factors in the adventitial vascular proliferation in HIV-associated vasculopathy ,, and KS angiogenesis, , to date, it remains unconfirmed whether the former is a de facto manifestation of KS.
|Table 1: Spectrum of Human immunodeficiency virus-associated vascular pathology |
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|Table 2: Vascular mural alterations in Human immunodeficiency virus-associated large artery vasculopathy|
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An underlying viral etiology for KS has been a long-held suspicion, , but it was only in 1994 that the genome of Human herpesvirus-8 (HHV8), also known as KS-associated herpes virus, was isolated from KS.  This discovery not only facilitated an improved understanding of KS but also heralded additional therapeutic and diagnostic possibilities.  In this context, the commercial availability of HHV8-latent nuclear antigen 1 (HHV8-LNA-1) immunohistochemical antibodies and HHV8 polymerase chain reaction (PCR) studies have played a crucial role in the diagnostic confirmation of KS, in all morphological stages of the disease and in challenging histodiagnostic settings. , While HHV8-LNA-1 immunohistochemical studies have the potential to confirm the etiopathogenetic role of HHV8 in the adventitial and peri-adventitial angioproliferation, and confirm whether the angioproliferative response represents KS or a reactive angioproliferation, such HHV8-LNA-1 studies have not been reported up to now.
This study describes the alterations of adventitial small vessels in the biopsies of HIV-vasculopathy and compares the adventitial changes to that in the angioproliferative confirmed early "patch" stage of cutaneous AIDS-associated KS. , HHV8-LNA-1 immunostaining of the vasa vasora, adventitial angioproliferation, and HHV8 PCR studies thereof are appraised to confirm whether the adventitial vascular proliferation is a tocsin of KS. The potential etiopathogenetic roles of the vasa vasorum and the local angio-inflammatory adventitial milieu are discussed in the context of HIV-vasculopathy.
| Materials and Methods|| |
Twenty HIV-vasculopathy resection specimens from ARV-naive, HIV-positive adult patients, 10 each with aneurysmal or occlusive disease, were retrieved from the archive of the Department of Vascular Surgery, University of KwaZulu-Natal and Anatomical Pathology, National Health Laboratory Service and University of KwaZulu-Natal, from January 01, 2007 to June 30, 2011. Microscopic sections of the aneurysmal wall, wall of the occluded segment, and adjacent normal-appearing vessel wall of all the sections were re-appraised as per [Table 2], with focus on the adventitial angioproliferation for the current study purposes. Ten biopsies of confirmed, early cutaneous KS from ARV-naive, HIV-positive adult patients, variably labeled as bruising, macular, and erythematous lesions were retrieved from the archive of the Department of Anatomical Pathology. Hematoxylin and eosin stained sections of the vascular resections and skin biopsies were re-appraised.
Immunohistochemical staining for HHV8-LNA-1 (Novocastra, Newcastle-Upon-Tyne, UK, clone13B10, 1:40 dilution) and endothelial cells using anti-human CD34 antibody (DakoCytomation, Glostrup, Denmark, clone QBEnd 10, 1:40 dilution) were undertaken on 3 μm thick vascular and aneurysmal wall and skin sections cut from archival wax blocks. The tissue sections were subjected to heat-assisted microwave antigen retrieval and manual polymer-based immunohistochemical staining with diaminobenzidine as the chromogen, using a standard immunohistochemical protocol with positive and negative controls.
PCR investigations for HHV8 were undertaken on the blood vessel section, as per in-house protocol with appropriate controls, based on internationally recommended protocols. Briefly, DNA was extracted from paraffin wax sections using the QIAamp FFPE DNA extraction kit (Qiagen, Valencia, CA, USA) according to manufacturer's instruction. The integrity of the extracted DNA was assessed by PCR for a reference gene followed by semi-nested PCR for the ORF25 gene of HHV8 using the following primers: Outer F 5'- gAAATTACCCACgAgATCgC-3', R 5'- AgCAgTgTATCCCACgTgATC-3' and inner F 5'- CATgggAgTACATTgTCAggACCTC-3'. PCR was performed on a CFX-96 (Bio-Rad, Hercules, CA, USA) thermal cycler using the FastStart Taq DNA polymerase PCR kit (Roche Bioscience, Palo Alto, CA, USA) according to manufacturer's instruction. Initial denaturation was undertaken at 95°C for 4 min with 40 cycles denaturation at 95°C for 30 s, annealing for 30 s (outer primers at 56°C and semi-nested primers at 58°C), and elongation for 30 s at 72°C. Final extension was undertaken for one cycle at 72°C for 5 min. PCR amplification products were separated on a 1.5% agarose gel.
Full ethical approval, including the use of archival data and stored tissue, was provided by the Institutional Review Board (the Bioethics Committee of the University of KwaZulu-Natal: Protocol BF208/11). Informed consent was obtained from all patients who were prospectively evaluated.
| Results|| |
The average age of patients with aneurysmal disease was 37.4 (range: 21-58) years. There were 9 males. The CD4 count, available in 7 patients, averaged 103 (range: 89-204) cells/μL. Viral loads, available in 2 patients were 23,700 and 41,200 copies/ml. The aneurysms involved the femoral (5), iliac (4), and common carotid (1) arteries.
The average age of the 10 male patients with occlusive disease was 35.4 (range: 29-53) years. The CD4 count, available in 8 patients, averaged 111 (range: 92-218) cells/μL. Viral loads, recorded in 3 patients, were 17,000, 28,000 and 59,000 copies/ml. The occlusive disease involved the femoral (6) and iliac (4) arteries.
The macroscopic specimens from 9 patients with aneurysmal disease encompassed wedge biopsies of the aneurysm (average size 12 [range: 8-23] mm) and separate biopsies of the adjacent vessel wall (average largest diameter 4.8 [range: 3-7] mm). One biopsy comprised the resected aneurysm and continuous proximal and distal adjacent wall, 3 and 4 mm in length, respectively. The thin-walled saccular aneurysm that contained organizing thrombus, measured 22 mm × 46 mm × 68 mm. Paravascular hematoma was also present.
The macroscopic specimens from 10 patients with occlusive disease encompassed excision biopsies of the occluded segment and the continuous adjacent proximal and distal patent vessel. The occluded segments were thick-walled and contained organizing thrombus. The average lengths of the proximal continuous adjacent vessel wall, recorded in 4 patients ranged from 3 to 6 mm and that of the distal component, ranged from 4 to 6 mm.
The biopsies from patients with established early cutaneous KS were 7 mm punch biopsies.
Microscopic sections of the adventitia of the aneurysmally dilated, occluded, or stenosed segments and the juxtaposed normal-appearing vessel wall demonstrated common histopathological findings. These included fibrosis and a proliferation of round or slit-like, capillary-caliber vasculature that dissected the adventitial collagen [Figure 1]a and b. The vasculature was lined by CD34-positive endothelial cells. There was mild variation in endothelial size, shape, and staining properties, but endothelial pleomorphism and papillary luminal tufting were not present. A variable admixture of lymphocytes, plasma cells, histiocytes, microhemorrhages, and hemosiderin [Figure 1]a was noted. Sections from the same micro-anatomical locations of four occlusive and six aneurysmal resections also demonstrated adventitial leukocytoclastic [Figure 1]c and lymphocytic vasculitis. In addition, all biopsies displayed intimomedial fibrosis and hypertrophy of the vasa vasora. In six specimens, vasa vasora thrombosis was noted. The inflammatory component was characterized by a perivascular and diffuse interstitial lymphoplasmacytic and histiocytic infiltrate. The media of all vessels demonstrated leukocytoclastic vasculitis, hemorrhage, hemosiderin, a perivascular lymphoplasmacytic, and histiocytic infiltrate and fibrosis. None of the biopsies demonstrated granulomatous inflammation. Immunostaining for HHV8-LNA-1 [Figure 1]d and HHV8 PCR tests was negative in all specimens.
Cutaneous biopsies of early KS demonstrated typical dermal angioproliferative and inflammatory alterations [Figure 2]a and b that were similar to that seen in the HIV-associated large vessel adventitial angio-inflammatory response, but vasculitis or thrombosis was not identified. The vasculature was lined by CD34-positive, variably pleomorphic endothelial cells. In contrast to the distinctive absence of an HHV8-LNA-1 immunohistochemical and molecular signature in the adventitial angioproliferation, HHV8-LNA-1 immunostaining highlighted positive endothelial and scattered dermal spindle cells in all cutaneous KS biopsies [Figure 2]c.
|Figure 1: (a) Adventitial slit-like vasculature lined by spindled endothelial cells (arrows), interstitial lymphocytes (arrowheads), and hemosiderin (encircled) (H and E, ×240), (b) congested vasculature and erythrocyte extravasation (H and E, ×240), (c) leukocytoclastic vasculitis with fibrinoid necrosis (arrows) (H and E, ×480), (d) Human herpesvirus-8-latent nuclear antigen-1 immunonegative spindled endothelial cells (arrows) (Human herpesvirus-8-latent nuclear antigen-1, ×480)|
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|Figure 2: (a) Cutaneous Kaposi sarcoma with dermal (asterisks) fibrosis and slit-like vasculature (H and E, ×120), (b) slit-like vasculature (arrows), inflammatory cells, and hemosiderin (arrowheads) (H and E, ×480), (c) Human herpesvirus-8-latent nuclear antigen-1 immunopositive spindled endothelial cells (arrows) (Human herpesvirus-8-latent nuclear antigen-1, ×480)|
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| Discussion|| |
The association of HIV infection with a spectrum of infectious and/or inflammatory vasculitides is well-established.  While primary HIV-associated systemic necrotizing vasculitis was reported early in the AIDS epidemic, , progressive AIDS-related immunodeficiency is also associated with a plethora of secondary, direct angio-invasive or host immune-mediated, infective vasculitides [Table 1]. ,, In contrast to the primary and secondary vasculitides that are not unique to HIV-infected patients, a unique form of pediatric HIV-associated multi-organ arteriopathy of small and medium-sized vessels was described in 1987 for the 1 st time.  This was followed by several reports on HIV-associated large vessel peripheral disease with aneurysmal and occlusive clinicopathological phenotypes. ,, Notwithstanding the heightened awareness and recognition of HIV-vasculopathy, the exact etiopathogenetic mechanisms have not been elucidated to date.  Direct invasion of the arterial wall by HIV, an immune complex mechanism and co-infection by a hitherto unrecognized infective partner, have been postulated. ,,, Occlusive and aneurysmal large vessel HIV-associated disease is characterized by a compendium of histopathological alterations [Table 2] with adventitial alterations recorded as one of the diagnostic histomorphological features. , The presence of leukocytoclastic vasculitis of adventitial and peri-adventitial vessels and proliferation of slit-like vessels within and dissection of the adventitial collagen has been well-documented. , Although mimicry of the latter to KS has been alluded to,  this has not been objectively investigated or revisited since the established association between KS and its infective etiological agent, HHV8.
KS was first described in 1872.  While it remained a rare disease with a predilection for Central Africa, parts of Eastern Europe and the Mediterranean region until the late 1980s, the AIDS epidemic increased, not only the incidence of KS, but also catapulted KS as the most common AIDS-associated malignancy.  In 1994, a breakthrough in the etiopathogenetic understanding of all forms of KS was realized when the causal association between HHV8 and KS was established.  HHV8-LNA-1 is a nuclear antigen that is expressed by all cells that are latently infected by the virus.  Subsequent studies by several workers established the specificity and sensitivity of HHV8 LNA-1 and its usefulness in the diagnosis and distinction of KS from its mimickers. , HHV8-LNA-1 immunohistochemistry is more reliable as it demonstrates the nuclear immunolocalization of the viral product, in contrast to PCR studies that may produce false positive results. , The latter may be traceable to HHV8 passenger lymphocytes and nonspecific amplification. , In addition, the discovery of HHV8 has therapeutic implications.  While HAART is a common treatment strategy for HIV suppression, it also impacts HHV8 suppression.  However, additional drugs that block herpesvirus DNA synthesis also inhibit HHV8 replication and are potential additional treatment options for HHV8-induced or co-induced disease, such as KS.  In the context of cutaneous KS, HHV8 LNA-1 has emerged as a pivotal marker for the diagnosis of early patch stage cutaneous lesions  that may not only resemble granulation tissue, but in the context of HIV-vasculopathy, also shares similarity with the adventitial angioproliferation.
The resemblance of the adventitial angioproliferation in HIV-vasculopathy to the dermal angioproliferation in cutaneous KS, , especially the patch stage disease, is germane, not only in the global literature on HIV-vasculopathy but also in this study. The similarity hinges on the capillary-caliber vascular proliferation and collagen dissection of the adventitia of vasculopathic vessels and dermal connective tissue in HIV-vasculopathy and cutaneous KS, respectively. Additional overlapping features include the lymphoplasmacytic cellular infiltrate, erythrocyte extravasation, microhemorrhages, and admixed siderophages. In contrast, the angioproliferation in KS differs from HIV-vasculopathy by the absence of leukocytoclastic vasculitis in cutaneous KS and the conspicuous absence of HHV8 endothelial illumination and negative HHV8 testing by PCR of HIV-vasculopathy. Apart from KS, several other diseases may demonstrate microvascular proliferation and collagenous angio-dissection in aortic adventitial and cutaneous dermal locations because of a locally induced hypoxic environment. , Similar to the possibilities raised for the adventitial and peri-adventitial vasoproliferation, Rongioletti and Rebora  have emphasized that the most important differential diagnosis of cutaneous reactive angiomatoses is patch stage KS. Exclusion of a neoplastic from a quasi-neoplastic process has management implications as control of the underlying cause of the vascular proliferation and revascularization may prove curative, and may serve as the tocsin of undeclared systemic occlusive or inflammatory vasculopathy. , Similar to HIV-vasculopathy, the exact pathogenesis of cutaneous reactive angiomatoses remains unconfirmed to date. Proposed mechanisms include occlusive or inflammatory vasculopathic processes that promote microthrombus formation, the genesis of a hypoxic milieu and induction of vascular endothelial growth factors (VEGFs) that stimulate extravascular endothelial proliferation. 
The adventitial angioproliferation that involves the vasa vasora has recently emerged as a significant role player in aortic pathology.  Although defined as a network or plexus of microvessels in arterial walls, vasa vasorum are functional end arteries.  Three types of vasa vasora have been described in experimental studies: Vasa vasorum externa, vasa vasorum interna, and the venous vasa vasora.  The vasa vasorum externa originate from major aortic branches and the vasa vasorum interna from the main lumen, but vena vasora drain the arterial wall into adjacent veins rather than into the wall of the parent vessel. , While the vessel wall thickness determines the distribution and extent of blood vessel vascularization by vasa vasora, the inner avascular third, approximately 0.5 mm in width, is supplied by luminal filtration, and is adequate for medial nutrition. The media of blood vessels beyond this zone require vasa vasora supplementation. , Different species have demonstrated different vasa vasorum development in the early weeks of embryonic development with increasing vasa vasorum volume with fetal growth.  Vessel formation includes two basic processes: Vasculogenesis and angiogenesis.  The former encompasses embryonic primary vascular plexus development from angioblasts whereas the latter occurs during embryonic development and in adults.  Angiogenesis occurs in physiological states, such as wound healing and in pathological states, such as solid tumor formation.  The members of the VEGF family of cytokines are important role players in angiogenesis. , VEGF-A and VEGF-A receptor are necessary for embryonic development and also regulate vascular permeability, proliferation, and new vessel survival. 
VEGF-A is expressed by HHV8-infected primary effusion lymphoma cell lines, and infection of endothelial cells with HHV8 leads directly to increased expression of VEGF-A.  While this offers a compelling and attractive potential pathomechanism for the adventitial angioproliferation and potential promise for allied therapeutic strategies, this study has demonstrated the absence of an HHV8 footprint in this context. Despite the clinicopathological heterogeneity, the adventitial angio-inflammatory and associated vasa vasora alterations are a consistent finding in HIV-vasculopathy. The current literature supports vascular proliferation as a function of the VEGF family of cytokines. ,,, Although VEGF-A shares a common pathogenetic role for the neoangiogenesis in HIV-vasculopathy as well as thrombotic and aneurysmal disease unrelated to HIV infection, ,, the exact stimuli of VEGF activation in HIV-vasculopathy are unreported.
Because of the nutritional role of the vasa vasorum interna and direct vessel wall perfusion from the vessel lumen, intraluminal thrombus and intimal expansion by fibrosis in the setting of occlusive and aneurysmal HIV-vasculopathy, may preclude adequate luminal perfusion of the vessel wall. These factors, together with the fibro-inflammatory obliterative alterations in the vasa vasora are hypothesized to increase hypoxic damage to the vessel wall,  that in turn, increases vasa vasorum proliferation through VEGF and other growth factors.  Unraveling the exact local and/or systemic triggers of the vasa vasorum pathology is pivotal, not only for an improved understanding of HIV-vasculopathy, but also for improved and perhaps, targeted, management thereof.  Whether HIV alone or in partnership with other infective agents, other than HHV8, are the triggers for the vasa vasorum aberrations require further investigation.
| Conclusion|| |
This study confirms the absence of an HHV8-induced cause for the adventitial angioproliferation that masquerades as KS microscopically. The role of vasa vasorum pathology and vascular obliteration as the stimulus for the adventitial angioproliferation is borne out in the phenotypic features of this study and earlier studies. , The hypoxic milieu is common to diseases typified by an angioproliferative phenotype and remains the pathogenetic pivot in the context of HIV-associated adventitial angioproliferation, but the exact interplay of direct and indirect etiological agents and cellular and subcellular pathogenetic factors require ongoing, perhaps accelerated, investigation for improved understanding of the disease and patient management.
We thank Mrs. M. Moodley for administrative assistance, Mr. Dinesh Sookhdeo for laboratory support, and the Medical Education Partnership Initiative for partial study funding.
Financial support and sponsorship
Medical Education Partnership Initiative provided partial study funding.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]