Kaposi Sarcoma

Not clinically relevant

There is serological correlation between HHV8 infection and KS. Not all seropositive individuals have KS; infection is required but not sufficient for disease induction, which results from a complex interplay of genetic, immunological, and environmental factors. Comparative genomic hybridization analyses show recurrent 11q13 involvement, including of FGF4 and FGF3 target genes. Y chromosome loss appears recurrent in early disease, whereas additional changes of chromosomes 16, 17, 21, X, and Y appear during tumor growth. KRAS and TP53 alterations are reported in addition to aberrant expression of genes related to neoangiogenesis and proliferation that may impact endothelial cell transformation by HHV8 (KS-associated herpesvirus). Both viral and cellular DNA-encoded microRNAs have been shown to play an important role in pathogenesis.

Skin lesions (patches, plaques, nodules) range from small to several centimeters. Involvement of mucosa, soft tissues, lymph nodes, and visceral organs presents as variably sized hemorrhagic nodules that can coalesce.

All four KS types show identical histological features. Early skin lesions show subtle vascular proliferation. In the patch stage, vascular spaces are increased in number, dissecting collagen fibers in the upper reticular dermis. Lining endothelial cells are flattened or oval, with no or minimal atypia. Pre-existing vessels may protrude into lumina of new vessels. Ovoid/spindle endothelial cell proliferations surround pre-existing vessels, and admixed lymphoplasmacytic infiltrates, extravasated erythrocytes, and hemosiderin deposits are common. Rarely, lesions resemble lymphangioma or hemangioma, causing diagnostic confusion. The papillary dermis is uninvolved in early stages. In the plaque stage, all patch-stage characteristics are exaggerated, and angioproliferation is extensive, with jagged vascular spaces. The inflammatory infiltrate is denser, with extravascular erythrocytes and siderophages, as well as frequent intracellular or extracellular hyaline globules. The nodular stage comprises circumscribed, cellular nodules of spindle cell fascicles with minimal atypia, hyaline globules, and numerous slit-like spaces containing erythrocytes, with peripheral ectatic vessels. Rare histological subtypes include anaplastic KS, which is clinically aggressive with increased metastatic potential, and intravascular KS.
In nodal disease, KS may be unifocal or multifocal and may entirely efface nodes. Early lesions may be subtle, showing only increased numbers of vascular channels with sinusoidal plasma cell infiltrates. In viscera, lesions tend to respect organ architecture and spread along native structures, such as pre-existing vessels, bronchi, and liver portal areas, before involving surrounding parenchyma.
Both lining endothelial cells of vessels and spindled tumor cells express endothelial markers, including CD31, CD34, and ERG, and lymphatic markers such as podoplanin (D2-40), and they show almost invariable nuclear expression of HHV8.

Not clinically relevant

Disease evolution depends on the epidemiological–clinical type and extent. Degree of immunosuppression at diagnosis is the most important survival determinant, but this is modified by treatment (including surgery, radiotherapy, and chemotherapy). Immunosuppression withdrawal can sometimes cause disease resolution. Combined HAART and systemic chemotherapy improves morbidity and mortality. Patients with widespread visceral involvement are commonly poorly responsive to treatment.

PCR and in situ hybridization show HHV8 in the flat endothelial cells lining vascular spaces and in spindle cells.

Essential: proliferation of small slit-like vessels lined by mildly atypical cells and surrounded by bland spindle cells; extravasated erythrocytes and lymphoplasmacytic patchy infiltrates in the early stage.

Desirable: nuclear HHV8 expression (by immunohistochemistry).