Virtually all KS lesions are infected by KSHV (HHV-8). Like Epstein-Barr virus, KSHV is a γ-herpesvirus. It is transmitted both through sexual contact and potentially via oral secretions and cutaneous exposures (of note, the prevalence of endemic African KS is inversely related to the wearing of shoes). KSHV and altered T-cell immunity probably are required for KS development; in older adults, diminished T-cell immunity may be related to aging. It also is probable that acquired somatic mutations in the cells of origin contribute to tumor development and progression.
KSHV causes lytic and latent infections in ECs, both of which probably are important in KS pathogenesis. A virally encoded G protein induces VEGF production, stimulating endothelial growth, and cytokines produced by inflammatory cells recruited to sites of lytic infection also create a local proliferative milieu. In latently infected cells, KSHV-encoded proteins disrupt normal cellular proliferation controls (e.g., through synthesis of a viral homologue of cyclin
D) and prevent apoptosis by inhibiting p53. Thus, the local inflammatory environment favors cellular proliferation, and latently infected cells have a growth advantage. In its early stages, only a few cells are KSHV-infected, but with time, virtually all of the proliferating cells carry the virus. As with EBV infection, early lesions are polyclonal but with accumulation of mutations the tumors become monoclonal.
MORPHOLOGYInclassicKaposisarcoma(andsometimesinothervariants),the cutaneouslesionsprogressthroughthreestages:patch,plaque, andnodule.
•Patches arepink,red,orpurplemacules,typicallyconfinedtothedistallowerextremities(
Fig.10.30A ).Microscopicexaminationrevealsdilated,irregular,andangulatedbloodvesselslinedbyECsandaninterspersedinfiltrateofchroniclaceous, raised plaques (
Fig.10.30A )composedofdilated,jaggeddermalvascularchannelslinedandsurroundedbyplumpspindlecells.Otherprominentfeaturesincludeextravasatedredcells,hemosiderin-ladenmacrophages,andothermononuclearcells.
•Eventuallynodular, moreovertlyneoplastic,lesionsappear.Thesearecomposedofplump,proliferatingspindlecells,mostlylocatedinthedermisorsubcutaneoustissues(
Fig.
10.30B ),oftenwithinterspersedslitlikespaces.ThespindlecellsexpressbothECandSMCmarkers.Hemorrhageandhemosiderindepositionaremorepronounced,andmitoticfiguresarecommon.Thenodularstageoftenisaccompaniedbynodalandvisceralinvolvement,particularlyintheAfricanandAIDS-associatedvariants.
The course of disease varies widely according to the clinical setting. Most primary KSHV infections are asymptomatic. Classic KS is—at least initially—largely restricted to the surface of the body, and surgical resection usually is adequate for an excellent prognosis. Radiation therapy can be used for multiple lesions in a restricted area, and chemotherapy yields satisfactory results for more disseminated disease, including nodal involvement. In KS associated with immunosuppression, withdrawal of therapy (with or without adjunct chemotherapy or radiotherapy) often is effective. For AIDS-associated KS, HIV anti-retroviral therapy generally is beneficial, with or without additional therapy. IFN-γ and angiogenesis inhibitors also have proved variably effective.
Hemangioendotheliomas comprise a wide spectrum of borderline vascular neoplasms with clinical behaviors intermediate between those of benign, well-differentiated hemangiomas and aggressively malignant angiosarcomas