Histological variants of cutaneous Kaposi sarcoma
© Grayson and Pantanowitz. 2008
Received: 23 July 2008
Accepted: 25 July 2008
Published: 25 July 2008
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© Grayson and Pantanowitz. 2008
Received: 23 July 2008
Accepted: 25 July 2008
Published: 25 July 2008
This review provides a comprehensive overview of the broad clinicopathologic spectrum of cutaneous Kaposi sarcoma (KS) lesions. Variants discussed include: usual KS lesions associated with disease progression (i.e. patch, plaque and nodular stage); morphologic subtypes alluded to in the older literature such as anaplastic and telangiectatic KS, as well as several lymphedematous variants; and numerous recently described variants including hyperkeratotic, keloidal, micronodular, pyogenic granuloma-like, ecchymotic, and intravascular KS. Involuting lesions as a result of treatment related regression are also presented.
Kaposi sarcoma (KS) is a vascular lesion of low-grade malignant potential that presents most frequently with skin lesions. Most histopathologists are au fait with the histologic picture of usual (typical) cutaneous KS as it progresses from patch, to plaque and finally nodular stages [1–4]. This morphologic spectrum of "usual" KS is common to classic, African endemic, transplant-associated, and acquired immune deficiency syndrome (AIDS)-associated KS . In recent decades, however, there has been an increasing awareness of a wider histologic spectrum [5, 6]. This has resulted in a growing number of reported clinical and/or histologic variants of KS. Failure to identify a given lesion as KS could lead to delayed diagnosis or inappropriate management. It has also been suggested that certain variants, such as anaplastic KS and possibly lymphangioma-like KS, might have prognostic relevance [7–9].
Taking these factors into account, we have elected to divide KS skin lesions into four broad groups: (1) KS lesions which encompass usual variants related to disease progression, (2) KS variants alluded to in the older literature, (3) more recently described KS variants, and (4) KS lesions as a consequence of therapy. Although the apparent histogenesis of some of these morphologic variants is known, the pathogenesis of others is uncertain or subject to speculation. Hyperkeratotic KS, by way of example, frequently occurs as a result of KS-associated chronic lymphedema of the lower extremities . Intravascular KS, on the other hand, could either originate primarily as an intravascular proliferation, or alternatively develop as a consequence of intravascular extension of a lesion breaching the vessel wall . KS lesions arising in extracutaneous locations often differ histologically from their counterparts in the skin, including the recent description of "in situ" KS involving mediastinal lymphatic vessels .
Large cutaneous nodules may frequently undergo ulceration. Superficial shave biopsies of such lesions may be diagnostically challenging to the histopathologist, as most of the specimen may contain only an inflammatory exudate with underlying granulation tissue; this may be misinterpreted as a pyogenic granuloma . Distinguishing between spindle cells from granulation tissue and lesional KS cells from the uppermost portion of an underlying KS nodule can be difficult, if not impossible without the aid of immunohistochemistry. The commercial antibody to HHV-8 LNA-1 and the lymphatic endothelial cell marker D2-40 may prove very useful in this context. Staining with these markers is preferable to less specific vascular markers such as CD31 or CD34, as these do not facilitate recognition of the lesional and non-lesional endothelial cell populations. Rare instances of acquired immune deficiency syndrome (AIDS)-associated KS harboring a concomitant opportunistic pathogen (e.g. cryptococcosis) may also go undiagnosed in superficial biopsy material [14, 15]. Superficial shave biopsies, therefore, should be discouraged.
Lesions that may potentially be confused histologically with nodular KS include bacillary angiomatosis, other vascular tumors (e.g. spindle cell hemangioma and Kaposiform hemangioendothelioma), fibrohistiocytic tumors (e.g. cellular, angiomatoid and atypical variants of fibrous histiocytoma, and dermatofibrosarcoma protuberans), resolving dermal fasciitis, spindle cell melanoma, and several other spindle cell mesenchymal neoplasms (e.g. cutaneous leiomyosarcoma) [1, 2, 4].
Anaplastic KS, sometimes referred to as pleomorphic KS, is poorly documented in the literature, possibly because of its rarity. Malignant transformation of KS, characterized by an increase in the number of mitoses and marked cellular pleomorphism, was first described in 1959 by Cox and Helwig . A "monomorphic" variant was identified by Templeton in several cases of African KS . In a review of KS cases from Uganda (in 1971), investigators distinguished KS with a "monocellular pattern" (resembling anaplastic KS) from a so-called "anaplastic variant pattern" (resembling angiosarcoma) . Anaplastic histology has been described in the context of classic, African, and AIDS-associated KS [7, 8, 19–24]. We are unaware of a report of this rare variant following iatrogenic immunosuppression.
It is easy to appreciate why a host of other malignant spindle cell neoplasms might be entertained in the histologic differential diagnosis, including certain sarcomas (e.g. leiomyosarcoma, spindle cell rhabdomyosarcoma, malignant peripheral nerve sheath tumor, fibrosarcoma), amelanotic spindle cell melanoma, and spindle cell carcinoma [14, 15, 20]. Angiosarcoma might also be considered, particularly if erythrocytes are identified between the markedly atypical spindled cells. A comprehensive panel of immunohistochemical stains is often required to rule out the aforementioned entities and confirm the presence of KS . It is plausible that a proportion of anaplastic KS cases reported in the earlier literature, prior to the advent of immunohistochemistry, might not have been true cases of KS after all.
There are several variants of lymphedematous KS, all of which can present clinically with a deceptive bulla-like appearance (Figures pending permission). The interchangeable terminology that has been used in the literature for these variants is confusing. An attempt to classify this issue has been made , and includes variants associated with ectatic lymphatics such as lymphangioma-like and lymphangiectactic KS, and/or due to the accumulation of superficial dermal edema such as the subepidermal and intraepidermal (lymphatic) bullous KS variants. Most of these variants usually contain an admixture of more stereotypical KS lesions. In those cases where these lymphedematous variants form the predominant or sole histological pattern, the diagnosis of KS may be problematic.
Lymphangioma-like KS (LLKS), also referred to as "lympangiomatous" KS, is an uncommon variant that may be encountered in all four major clinicopathologic groups of KS patients [27–33]. Furthermore, lymphangioma-like morphology can occur in patch, plaque or nodular stage lesions . This variant is said to account for less than 5% of KS cases . Although Ronchese and Kern in 1957 are often credited with first describing the condition, the first reported case actually appears to date back to 1923, noted in a 66-year-old woman with clinical bullous KS lesions, the histology of which was described as being analogous to lymphangioma circumscriptum [27, 34]. LLKS is most likely related to lymphedematous KS, bullous KS and hyperkeratotic (or verrucous) KS, as many of the reported patients with these clinical variants of KS have shown histopathologic features of LLKS on skin biopsy [10, 26, 27, 34–39]. In some case reports patients with LLKS manifested with widespread and pronounced lymphedema  as well as effusions .
The only description of intravascular KS is limited to a report of six cases, including four patients with classic KS and two with AIDS-associated KS . Histologic examination in this small series showed an exclusively intravascular solid spindle cell KS proliferation. Immunohistochemical stains for desmin and smooth muscle actin (SMA) confirmed that this proliferation was indeed intravenous. The histologic differential diagnosis includes intravascular papillary endothelial hyperplasia, intravenous PG, intravascular fasciitis, papillary intralymphatic angioendothelioma (Dabska tumor) and intravascular myopericytoma .
Therapy may result in KS regression, and less likely exacerbation (so-called KS flare) . The histopathology of regression in KS has been previously described and is discussed below. KS exacerbation (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 . The histomorphology of KS flare lesions has yet to be described.
KS clearly has the ability to develop into lesions of varying morphologic appearance. It is important to be able recognize these variants in order to avoid potential misdiagnosis and improper management of afflicted patients. KS has been shown to be of lymphatic origin . This may explain the intimate association of abnormal lymphatics observed in several of these variants, such as lymphangioma-like and lymphangiectatic KS. KS is also intimately associated with lymphedema. Chronic lymphedema may even precede KS lesions. Some authors believe that chronic lymphedema may promote KS development due to a combination of collateral vessel formation, lympahngiogenesis and immune impairment . Hyperkeratotic and bullous KS variants can be attributed to the long standing effects of tumor-associated lymphedema on the overlying epidermis. Deep dermal fibroma-like nodules seen in cases associated with marked lymphedema could explain the origin of micronodular KS. The clinical significance of most of these KS variants has not been studied. Lymphedematous variants have been postulated to portend a poor prognosis. This is certainly plausible given the fact that significant KS-related edema carries a grave prognosis . Anaplastic KS is perhaps the only variant associated with aggressive behaviour. The reason for progressive histological dedifferentiation in some cases of KS is unknown. Studies looking at the role of HHV-8 and the host (e.g. immunity) in anaplastic cases may provide some answers.
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