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Pathology of Kaposi's sarcoma.

INTRODUCTION

Kaposi's sarcoma (KS) is a multifocal low-grade vascular tumour that may involve the skin, mucosa and viscera. The aetiological agent necessary for KS development is Kaposi's sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8). KS is currendy the most prevalent malignancy encountered among parients with AIDS worldwide. Despite the widespread use of highly active antiretroviral therapy (HAART) and chemotherapy, KS continues to be a problem [1]. Four epidemiological/clinical forms of KS are currently recognised: classic, African (endemic), AIDS-associated (epidemic) and iatrogenic (predominantly transplant-associated). KS exhibits unique pathological features at the gross, microscopic and ultrastructural levels. An appreciation of KS pathology is necessary in order to better understand the pathogenesis of KS progression, exacerbation and regression. Familiarity with KS pathology is also essentia] to accurately interpret experiments employing localisation studies (e.g. immunohistochemistry and in situ hybridisation) used to identify novel mechanisms of tumour development and/or therapeutic targets in KS tumour cells. Moreover, familiarity with KS lesions in vivo is helpful in order to appropriately interpret and extrapolate in vitro findings and the results obtained from studying animal models of KS. This review highlights several key features of KS pathology including aspects related to the investigational pathology of KS.

HISTORICAL PERSPECTIVE

KS was first described as 'idiopathic multiple pigmented sarcoma' by the Viennese dermatologist Dr Moritz Kaposi (1837-1902) [2]. His original paper in 1872 described KS progression from the extremities to involve the trunk, face, mucosa and viscera. A post mortem examination was performed in one case, in which Dr Kaposi found characteristic widespread KS lesions. He also described the histopathology in two cases as nodular groups of 'small round cells' in the dermis accompanied by haemorrhage and abundant pigment (presumably haemosiderin). In 1889, a description of infiltrating 'spindle-shaped cells' in the skin corroborated the sarcomatous nature of KS [3]. In 1899, the origin of KS from lymphatic endothelium was first proposed [4]. Researchers around this time also speculated that KS probably resulted from a 'chronic infection' that induced vessel proliferation and blood cell extravasation [5,6]. In 1950, McCarthy and Pack first reported on the typical histopathological evolution of KS lesions from an early 'inflammation-likemacule' into asarcomatous stage [7], Early work using enzyme histochemistry led researchers to postulate that the multicentric 'neotransformation' of lymphatics was the primary process in the histogenesis of KS [8], Once immunohistochemistry became available, investigations introduced helpful diagnostic markers (e.g. LNA1 for HHV8 detection), as well as a means to monitor biomarker expression in procured tissue for potential therapeutic targets. The first in vitro KS experiments began around 1910 [9]. Ensuing work in 1938 involved KS cultures with tissue implantation performed under the skin of a patient [10]. Today, several cell lines and animal models have been successfully established to study KS.

HISTOLOGY

HIV co-infection acts in a synergistic fashion with HHV8, resulting in more aggressive and widespread KS disease. This occurs because HIV both promotes HHV8 replication indirectly by impairing host immunity, and also plays a direct role in KS tumorigenesis through the production of cytokines and the HIV-1 transcriptional transactivator (Tat) protein. However, the histopathology of KS is essentially identical in the different epidemiological KS types [11,12]. This is not surprising given that lesional cells derived from classic and AIDS-related KS reveal identical cytochemical and molecular properties in vitro [13]. Nevertheless, a few studies have documented minor his top a tho logical differences between AIDS-associated KS and non-HIV associated KS cases [14-16]: lesional cell mitoses and cellular anaplasia are surprisingly more common in HIV-negative patients, whereas KS lesions in HIV-positive patients tend to display more extensive dissecting vessels. Depending upon the host inflammatory milieu, KS lesions may progress or regress. Exacerbation (KS flare or recrudescence) can occur following therapy with corticosteroids, after treatment with rituximab, or as part of the immune reconstitution inflammatory syndrome (IRIS) seen with antiretroviral therapy in HIV-infected persons [17].

PROGRESSION

Based upon clinical and corresponding histological findings, developing KS lesions undergo three stages of growth [18,19]. KS lesions evolve from early (patch stage) flat macules into plaques (plaque stage), and subsequently nodular lesions (tumour stage). Similar KS stages apply to both cutaneous and mucosal lesions [20,21]. Different histological stages can coexist concomitantly in the same individual at the same time, and even in the same crop of lesions. The spectrum of KS has recently been expanded to include pre-KS lesions, also referred to as a lymp ho edematous or in situ form of KS [22-24]. Such pre-KS lesions are characterised by groups of abnormal capillary-like vessels admixed with an inflammatory infiltrate. They are believed to be associated with lymphangiogenesis arising in the setting of chronic lymphoedema [25].

Early histological changes may be inconspicuous, and for that reason can be easily dismissed on biopsy by the unwary [26]. Early KS lesions are seen most commonly in the AIDS patient [27]. Patch stage KS is characterised by a dissecting dermal proliferation of ramifying, small, abnormal (jagged) vessels lined by thin endothelial cells, often surrounding larger ectatic vessels and skin adnexa, producing the so-called promontory sign (Figure 1A). At this early stage, a sparse chronic inflammatory infiltrate, extravasated red blood cells, and haemosiderin-laden macrophages are frequently present. In plaque stage KS, there is a proliferation of spindle cells that, together with larger vessels, begin to involve most of the dermis (Figure IB), and in some cases even the subcutis. Spindle cells appear to be the central masterpiece in KS tumorigenesis [28]. Well-developed KS tumours form nodules (Figure 1C) composed predominantly of fascicles of spindled-shaped tumour cells (Figure 1D). Typical KS lesions are devoid of marked cellular pleomorphism and a significant number of mitotic figures. Apoptosis is an infrequent finding [291. Spindled cells are admixed with abnormal vessels and a variable chronic inflammatory infiltrate comprising lymphocytes, plasma cells and dendritic cells [30].

HHV8 infection alone is insufficient for the development of KS. Chronic inflammation associated with KS plays an important role in tumour pathogenesis [31]. HHV8 infection of KS lesional and inflammatory cells results in the production of several pro-inflammatory and angiogenic cytokines (e.g. viral interleukin-6) and chemokines (e.g. vCCL-1 or K6, vCCL-2 or K4, and vCCL-3 or K4.1). Chemokine receptors (such as CCR1, CCR2, CCR5, CXCR3, and CXCR4) are expressed by KS spindle cells. Also of great relevance to KS development is the viral G protein-coupled receptor (vGPCR), a homologue of the human IL-8 receptor (CXCR2). The constitutive activity of vGPCR induces a myriad of signalling molecules, like NF[kappa]B, which leads to the production of several pro-inflammatory cytokines including the interleukins (IL) IL-1B, IL-6, IL-2, IL-4, IL-8 as well as TNF[alpha], RANTES, GM-CSF, and the adhesion molecules VCAM-1, ICAM-1 and E-selectin. Constant signalling from tumour tissue is a major stimulus for both proliferation and chronic infiltration of KS by leukocytes. These leukocytes, in turn, secrete further cytokines, chemokines, enzymes, and growth factors that favour the growth of HHV8-infected cells, and thereby contribute to KS progression [31].

Eosinophilic hyaline globules are a common finding in advanced KS lesions (Figure 2A). These globules may be seen extracellularly or located within the cytoplasm of perivascular cells, spindle-shaped cells and occasionally in endothelial cells lining vessels or slit-like spaces [32]. KS lesions at all stages of development also frequently contain haemosiderin-laden macrophages and iron (Figure 2B). Iron staining, as well as immunohistochemical HHV8 staining, is a reliable marker for KS compared with interstitial granuloma annulare, a mimic of early KS [33]. The source of this lesional iron is believed to be derived from extravasated red blood cells [34]. Investigators have suggested that iron is an important co-factor in KS pathogenesis [35,36]. Epidemiological data in support of this idea comes from the observation that areas of endemic KS in Africa and classic KS in the Mediterranean appear to be confined to geographic zones with iron oxide-rich volcanic clays. Further work on the role of iron and related compounds (e.g. heme oxygenase-1) in KS pathogenesis and the benefit of iron chelators is necessary.

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REGRESSION

KS regression can rarely occur spontaneously, after the withdrawal or decreasing immunosuppression in transplant recipients, and more commonly following antiretroviral treatment and/or systemic chemotherapy [17,37]. Clinical features of regression include flattening of lesions, reduction in lesion size, and change from a purple-red appearance to an orange-brown macule. Regressed KS lesions may deceptively mimic pigmented purpura. In mice, histological examination of paclitaxel-treated KS-like lesions showed a central regressing area of necrosis and an inflammatory cell infiltrate comprising macrophages and neutrophils [38]. Regressed KS lesions can be divided histologically into partial and complete regression [37]. Partially regressed lesions exhibit a significant reduction of spindle cells. Completely regressed lesions are characterised by an absence of detectable spindle cells, often accompanied by a slight increase in capillaries of the superficial plexus. All stages of regression are accompanied by a prominent perivascular lymphocytic infiltrate and abundant dermal haemosiderin-laden macrophages. Hyperpigmentation of regressed KS lesions is attributed to the accumulation of dermal siderophages. This may be cosmetically disconcerting for treated patients. Des mo plastic-like fibrosis around the periphery of regressing lesions has been documented by some authors [39]. However, prominent scar formation has only been reported in KS lesions treated with intralesional drugs.

VARIANTS

Several clinical and/or histological variants of KS have been described (figure 3) [40]. Many of these variants contain an admixture of more stereotypical KS lesions. However, in those cases where KS variants form the predominant or sole histological pattern, the diagnosis may be problematic. Certain variants, such as anaplastic KS and lymphangioma-like KS, might have prognostic relevance.

Anaplastic (pleomorphic) KS

This variant of KS is clinically notable for its high local aggressiveness on acral sites resulting in deep invasion, and increased metastatic capacity [411. Progressive histological dedifferentiation in typical cases of KS has been noted [42]. Anaplastic KS tumours form solid sheets of spindle cells (Figure 3A). They display a significantly greater degree of nuclear and cellular pleomorphism with many more mitoses than conventional nodular KS. Necrosis may also be observed.

Lymphoedematous variants

All of these variants can present clinically with a bulla-like (pseudoblister) appearance [43-47]. They include lesions associated with ectatic lymphatics (lymphangioma-like and lymphangiectactic KS) and those that have an accumulation of superficial dermal oedema (bullous KS). Lymphangioma-like KS, also referred to as lymphangiomatous KS, contains ectatic and interanastomosing vascular channels frequently devoid of erythrocytes (Figure 3B). In lymphangiectactic KS there are much large intratumoral and peritumoral dilated thin-walled lymphatic vessels (Figure 3C). Bullous KS is due to true subepidermal or intraepidermal bullae arising in concert with KS.

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Telangiectatic KS

This is a rare variant in which nodular KS lesions contain large, intensely congested, ectatic vascular spaces. These large spaces are lined by endothelial cells whose nuclei are immunoreactive for LNA1, implying that they are an integral part of the KS lesion, and not merely native dermal vessels that have undergone telangiectasia as a consequence of compression by the dermal tumour [40].

Hyperkeratotic (verrucous) KS

These KS lesions are related to severe KS-associated lymphoedema [48,49]. There is verrucous epidermal acanthosis and hyperkeratosis overlying an often fibrotic epidermis (Figure 3D). In view of the latter feature, diagnostic KS lesional tissue located in the deep dermis may be missed in superficial shave biopsies. Infrequently, such changes may involve an entire extremity manifesting as elephantiasis nostras verrucosa [50].

Keloidal KS

These lesions are firm and rubbery, caused by a prominent dermal expansion of dense, hyalinised collagen [51] with a distinct resemblance to a keloid (Figure 3E). The spindled KS proliferation may be easily obscured. The histological differential diagnosis includes a dermal scar at the site of a previous skin biopsy of a KS lesion.

Micronodular KS

This is a variant of nodular KS characterised histologically by a small, unencapsulated, circumscribed spindle cell proliferation in the reticular dermis [52]. These small lesions may be removed in their entirety by a punch biopsy.

Pyogenic granuloma (PG)-like KS

When small superficial KS nodules or micronodular KS lesions protrude from the skin they may elicit the development of a peripheral epidermal collarette, forming a PG-like KS lesion. [53]. If traumatized, these ulcerated lesions could potentially be misdiagnosed as a true PG (lobular capillary haemangioma). PG-like KS may very much resemble bacillary angiomatosis [54].

Ecchymotic KS

The intradermal KS proliferation in this variant is accompanied by extensive red blood cell extravasation (Figure 3F) [55]. The resulting marked purpura may obscure the underlying histological features of KS. The differential diagnosis includes intralesional haemorrhage brought about the biopsy procedure itself.

Intravascular KS

In these lesions, a solid spindle cell KS proliferation is exclusively intravascular [56].

Other variants

Other contemporary KS variants include glomeruloid KS, pigmented KS, and KS with myoid nodules [57].

CYTOLOGY

Taking into consideration the high prevalence of AIDS and limited resources for diagnosis in developing countries of Africa, fine needle aspiration (FNA) cytology appears to be a useful method for the diagnosis of KS [58-60]. Aspirates can be obtained from skin, enlarged lymph nodes, oral cavity lesions, as well as soft-tissue and visceral masses. Most smears have a bloody background in which intact to loosely cohesive clusters of bland spindle-shaped cells are distributed (Figure 4) [61,62]. Closely packed spindle cells are usually overlapping and have indistinct cytoplasmic borders. Vascular spaces containing blood and metachromatic globular structures that correspond to the eosinophilic globules seen in histological sections may rarely be present. Other spindle-cell lesions encountered in the HIV setting (e.g. mycobacterial spindle cell pseudotumour and leiomyosarcoma) need to be considered in die differential diagnosis. In difficult cases, ancillary studies (e.g. detection of HHV8) may be necessary [63].

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ULTRASTRUCTURE

The earliest reported electron microscopic study of KS was in 1962 [64]. Since then, several studies have reported on the ultrastructure of KS lesions [65,66]. Using scanning electron microscopy KS has a sponge-like appearance in which several angiogenic patterns may be observed [67,68]. With transmission electron microscopy, KS spindle-shaped cells can be seen forming vessels of varying size and integrity. These spindled cells demonstrate a spectrum of endothelial cell ultrastructure, resembling lymphatic and blood vascular endothelium, with occasional Weibel-Palade bodies and gap junctions reported by some authors [69,70]. As the histological stage of KS progresses and spindle cells begin to proliferate, the vascular endothelium undergoes dissolution of the basal lamina, intercellular junctions diminish, and the number of Weibel-Palade bodies is reduced [71]. In general, KS spindle cells have a paucity of cell organelles [72]. Compact rubroreticular structures appear to be an ultrastructural marker specific for AIDS-associated KS [73]. Several other non-specific ultrastructural findings within KS tumour cells have been reported, such as intracisternal crystalline inclusions, acanthosomic vesicles, and test-tube inclusions [74]. KS spindle cells appear to behave as facultative phagocytes, internalising and processing necrotic cells and red blood cells {figure 5}. These intracellular fragmented erythrocytes are believed to be equivalent to the hyaline globules seen by light microscopy [75]. Electron microscopy has also been used to confirm the relationship between hhv8 and KS. In this way, the ultrastructural details of hhv8 attachment, fusion, internalisation and transport within endothelial cells have been studied [76,77]. Of interest, investigators have reported the presence of bacteria and fungi within KS tumours identified by electron microscopy [78,79]. Their pathogenic significance remains unknown, but may merely reflect contamination from environmental micro-organisms.

IMMUNOHISTOCHEMISTRY

Immunohistochemistry (IHC) is the application of antigen-antibody interactions to histochemical techniques. Over 100 different primary andbodies have been evaluated using IHC on KS specimens in order to unravel the histogenesis of KS, understand its pathogenesis, facilitate diagnosis, and help identify novel therapeutic targets [80]. Most IHC studies have shown that KS lesional cells express endothelial antigens based upon their immunoreactivity for Ulex europaeus agglutinin-1 (UEA-1), thrombomodulin, factor VIII-related antigen (von Willebrand factor), CD31 (also called PECAM-1 for platelet endothelial cell adhesion molecule) (Figures 6A,B), and CD34 [81,82]. Factor VIII-related antigen is synthesised and stored in the Weibel-Palade body of vascular endothelium. The cellular origin (histogenesis) of KS lesional cells is controversial. Blood vessel endothelium, lymphatic endothelium, neural cells, dendritic cells, macrophages, fibroblasts and smooth muscle cells have all been professed to be the cell of origin for KS tumour cells. More recent studies have demonstrated that KS spindled cells express several lymphatic specific markers such as D2-40 (which binds to the podoplanin antigen), LYVE-1 (a homologue of the CD44 glycoprotein receptor for hyaluronan), VEGFR-3 (the receptor for VEGF-C), and Prox-1 [83,84]. Corroborative data has come from investigators showing that gene expression profiling of KS tumour cells closely matches that of lymphatic endothelial cells [85,86]. Part of the confusion and explanation for discrepant IHC results to date may be attributed to the fact that HHV8 infection appears to reprogram blood endothelial cells towards a lymphatic expression profile.

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Cytomegalovirus (CMV) and several human papilloma viruses (HPV) were initially proposed as potential aetiological agent of KS. HHV8 infection is now known to be necessary for the development of all KS epidemiological subtypes [87,88]. Apart from molecular detection methods, HHV8 can be identified and localised within KS lesional cells using IHC. One study reported KS spindle cells with targetoid intranuclear inclusions of the herpes viral type that investigators attributed to HHV8 infection [76]. While HHV8 occurs in a latent and lytic phase, both of which are necessary for oncogenesis, only minor viral lytic gene products are detectable in KS tumours. The commercial monoclonal antibody therefore most often used for this purpose is directed against the C-terminus of LNA1 (latency-associated nuclear antigen or LANA1) encoded by ORF-73. LNA1 immunoreactivity in KS cells typically appears as stippled nuclear staining (Figure 6C). Mature endothelial cells of normal blood vessels present in or adjacent to KS lesions have been shown to be consistendy negative for LNA1 in all cases studied [89]. LNA1 immunoreactivity is of great benefit in confirming a histopathological diagnosis of KS in unusual variants (Figure 6D). Also, positive immunoreactivity for LNAI has proved to be a useful diagnostic marker to help differentiate KS from its mimics [90-92]. However, HHV8 is not entirely limited to KS, and as such it has been detected in some angiosarcomas, haemangiomas and dermatofibromas [93]. Molecular methods of detection (e.g. PCR) for HHV8 maybe misleading, as inflammatory cells that harbour this virus may be included in samples of KS tissue. HHV8 can also be found in B-cells, T-cells, macrophages and perhaps circulating endothelial cells in KS patients. Productively infected monocytes within KS lesions are thought to be an important reservoir for transmission of HHV8. HHV8 immunoreactivity appears to be unaffected by HIV status, patient age, gender, tumour recurrence, or the site of the KS lesion [95].

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LIRON PANTANOWITZ (1), WAYNE GRAYSON (2), THIERRY SIMONART (3) AND BRUCE J DEZUBE (4)

(1) Department of Pathology, Baystate Medical Center, Tufts University School of Medicine, Springfield, MA, USA

(2) Department of Dermatology, Erasme University Hospital, Brussels, Belgium

(3) Ampath Laboratories, Johannesburg and Division of Anatomical Pathology, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa

(4) Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

Correspondence to: Liron Pantanowitz, Department of Pathology, Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199, USA. (email: liron.pantanowitz@baystatehealth.org)
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Title Annotation:LEADING ARTICLE
Author:Pantanowitz, Liron; Grayson, Wayne; Simonart, Thierry; Dezube, Bruce J.
Publication:Journal of HIV Therapy
Article Type:Clinical report
Geographic Code:1USA
Date:Jun 1, 2009
Words:5457
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