Patch stage KS, which represents the earliest phase in the evolution of cutaneous KS, is perhaps the histologic variant with the greatest propensity to cause diagnostic difficulties for the unwary. The initial low-power impressions are those of a "busy" dermis, or perhaps some form of mild inflammatory dermatosis 113. On closer examination, however, there are signs of a subtle vasoformative process composed of newly formed slit-like or somewhat jagged vascular spaces, which tend to be more conspicuous in the immediate vicinity of native dermal vessels and cutaneous appendages 1234. The protrusion of these native microscopic vascular structures into the lumens of more ectatic neoplastic channels results in the characteristic promontory sign (Figure 1). The intervening dermis frequently reveals dissection of its collagen bundles by slit-like vascular spaces lined by a monolayer of relatively banal, flattened endothelial cells, with a variable degree of erythrocyte extravasation. The newly formed channels often contain red blood cells. There is also a noticeable mild background inflammatory cell infiltrate comprising lymphocytes and plasma cells, often accompanied by a contingent of hemosiderin-laden macropahges. The aforementioned mononuclear cells tend to be concentrated around the native vessels and skin adnexal structures 1234.

In plaque stage lesions of KS, the histologic picture is characterized by a more diffuse dermal vascular infiltrate, accompanied by greater cellularity and occasional extension of this process into the underlying subcutaneous adipose tissue. The lesional cells tend to be more spindled and arranged in short, sometimes haphazard fascicles 1234. Fascicles cut in cross section demonstrate a sieve-like appearance. Mitotic figures are sparse and there is no significant nuclear or cytological pleomorphism. Intra- and extracellular hyaline globules, probably representing effete erythrocytes, are often seen. Careful scrutiny will frequently reveal "autolumination", whereby an erythrocyte is contained within a clear paranuclear vacuole in the cytoplasm of a spindled endothelial cell observed in cross section (Figure 2). Numerous dissecting vascular channels containing erythrocytes occupy the intervening dermis, and once again there is evidence of a background plasma cell-rich contingent of chronic inflammatory cells with admixed siderophages and free-lying hemosiderin pigment. The promontory sign, as described above, may also be encountered 1234. The histologic differential diagnosis includes tufted angioma, targetoid hemosiderotic hemangioma, microvenular hemangioma and acroangiodermatitis ("pseudo-Kaposi's sarcoma") 124.

The nodular form of KS usually poses no diagnostic difficulties. Occasionally, however, a small ulcerated nodular KS lesion may be mistaken for a pyogenic granuloma 1. Nodular KS exhibits dermal expansion by a relatively circumscribed, variable cellular proliferation of neoplastic spindled cells arranged in fascicles (Figure 4) 1234. Erythrocytes are contained within slit-like channels between the individual spindled cells. Although careful inspection may reveal occasional mitoses, the lesional cells are relatively monomorphic. Hyaline globules are seen more readily, as is the phenomenon of autolumination. In larger punch biopsy or excision biopsy specimens, the dermis away from the tumor nodule frequently exhibits changes associated with plaque stage KS, thus supporting the notion that patch, plaque and nodular stage lesions form part of a morphologic continuum. The periphery of some nodular KS lesions may show more dilated vascular spaces, imparting a pattern that is strikingly reminiscent of a cavernous hemangioma (Figure 4) 2. These larger, congested channels are an integral part of the lesion, as confirmed by positive immunohistochemical staining of the lining endothelial nuclei for HHV-8 latent nuclear antigen 1 (LNA-1).

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 1. 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 1415. 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) 124.

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 16. A "monomorphic" variant was identified by Templeton in several cases of African KS 17. 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) 18. Anaplastic histology has been described in the context of classic, African, and AIDS-associated KS 78192021222324. We are unaware of a report of this rare variant following iatrogenic immunosuppression.

Anaplastic KS is clinically notable for its high local aggressiveness, propensity for deep invasion, and increased metastatic capacity. Progressive histologic dedifferentiation in otherwise typical cases of KS has been noted (Figure pending permission) 2225. AIDS-associated tumors with anaplastic histology appear to have a propensity to occur in acral locations. In anaplastic KS, there is inherent potential for misdiagnosis as the vasoformative nature of the solid and frequently fascicular spindle cell proliferation is not readily apparent. This variant displays a significantly greater degree of nuclear and cellular pleomorphism than conventional nodular KS (Figure 5). In addition, there is an increased mitotic index (e.g. 5–20 mitoses per 10 high-power fields), and atypical mitoses may be encountered. Necrosis is occasionally observed.

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 141520. 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 15. 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 26, 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.

There is a single case report of telangiectatic KS, which occurred in a man with thymoma and myasthenia gravis receiving long-term immunosuppressive therapy 43. The term "telangiectatic" referred to the significant telangiectasia associated with the multiple cutaneous nodules, and not the histopathologic features thereof. The histopathology in this case report showed usual features of nodular KS, with no conspicuous background vascular ectasia 43. The authors have encountered rare histological examples of telangiectatic KS in which nodular KS lesions contained large, intensely congested, ectatic vascular spaces (Figure 11). Since these large spaces are lined by endothelial cells (Figure 12) whose nuclei are immunoreactive for LNA-1, it must be assumed that they are an integral part of the KS and not merely native dermal vessels that have undergone telangiectasia as a consequence of compression by the dermal tumor.

Hyperkeratotic KS is a rarely described clinicopathalogic variant of KS, which appears to be closely linked to severe KS-associated lymphedema in patients with AIDS 103544. There is verrucous epidermal acanthosis and hyperkeratosis overlying an often fibrotic epidermis (Figure 13). In view of the latter feature, diagnostic KS lesional tissue may be located at a relatively deeper level in the dermis, further emphasizing the potential inadequacy of superficial shave biopsies. On occasion, verrucoid epidermal changes may occur with LLKS histology (Figure 14). Infrequently, such changes may involve the entire lower extremity manifesting as elephantiasis nostras verrucosa 45. Chronic lymphedema may itself give rise to verruciform epidermal hyperplasia and hyperkeratosis, with increased fibroblastic activity, blood vessels and thick-walled lymphatic vessels throughout the dermis 39. Lympedematous AIDS-associated KS may also be associated with exophytic fibroma-like nodules, characterized by dermal fibrosis, a loose arrangement of fibroblasts and collagen bundles, and dilated blood vessels and lymphatic channels 103944.

The description of this exceedingly uncommon KS variant is limited to a 1994 report of three cases 46. Lesions are firm and rubbery, and may be linear 6. Histologically, there is notable dermal expansion by dense, hyalinized collagen with a distinct resemblance to a keloid (Figure 15). In such lesions the spindled KS proliferation may be obscured by these keloidal alterations. The histologic differential diagnosis includes a dermal scar at the site of a previous skin biopsy of a KS lesion. It is postulated that cytokines play a key role in the evolution of the keloidal stromal changes in this unusual variant 46.

Micronodular KS (Figure 16) is a recently described variant of nodular KS, which is characterized histologically by a small, unencapsulated, circumscribed spindle cell proliferation in the reticular dermis 47. Although the paper by Kempf et al described micronodular cutaneous lesions in a patient with classic KS 47, similar lesions are occasionally encountered in the context of AIDS-associated KS, and are often removed in their entirety by a punch biopsy.

Small, superficially located nodular or micronodular KS lesions may be protuberant and thereby elicit the development of a peripheral epidermal collarette (Figure 17). Such lesions have been referred to as pyogenic granuloma (PG)-like KS 48. Traumatized lesions may undergo ulceration and become inflamed, and potentially misdiagnosed as a true PG (lobular capillary hemangioma). To further complicate matters true PGs may themselves harbor kaposiform areas. PG-like KS must also be distinguished from bacillary angiomatosis, as some examples of the latter can adopt striking PG-like low-power architecture 1415.

In the variant referred to as ecchymotic KS, the intradermal KS proliferation is accompanied by extensive red blood cell extravasation (Figure 18) 49. The marked purpura often obscures the underlying histologic features of KS. The differential diagnosis includes intralesional hemorrhage brought about the biopsy procedure itself. Clinically, this variant of AIDS-associated KS manifests with ecchymotic or pityriasis-like patches 49. Ecchymotic plaque lesions may clinically also resemble a bruise or port-wine stain. A rare case of clinical "hemorrhagic" KS has been reported 50. However, it is unclear if the appearance in this case was attributed to extensive erythrocyte extravassation.

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 11. 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 51.

Therapy may result in KS regression, and less likely exacerbation (so-called KS flare) 52. 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 52. The histomorphology of KS flare lesions has yet to be described.