Lymphatic Phenotype Predominates in Cutaneous Kaposi Sarcoma: A Dual Immunohistochemical Analysis of HHV8-Positive Cells

Abstract:

Kaposi sarcoma (KS) is a low-grade endothelial neoplasm whose definitive lineage—blood vascular versus lymphatic—remains controversial. This ambiguity stems from the tumor's known coexpression of both blood (eg, CD31 and CD34) and lymphatic (eg, podoplanin) endothelial markers. To clarify the phenotype of the neoplastic population, we developed novel dual immunohistochemistry protocols (HHV8/podoplanin and CD31/podoplanin) to specifically evaluate marker coexpression within HHV8-infected spindle cells. The assays were applied to a series of 13 KS lesions (from 12 patients). Coexpression of HHV8 (nuclear) with podoplanin or CD31 (cytoplasmic) was assessed using a semiquantitative scoring system (0: 0%; 1: 1%–10%; 2: 11%–50%; 3: 51%–100%). In all 9 cutaneous KS lesions, HHV8-positive cells demonstrated strong, uniform coexpression with the lymphatic marker podoplanin (mean score 3.0) across all histologic stages. By contrast, coexpression of HHV8 with the blood vascular marker CD31 was significantly weaker and more variable (mean score 1.0; P = 2.0E-07). Notably, this differential pattern was not observed in mucosal KS; the 3 mucosal lesions analyzed showed equally strong coexpression of HHV8 with both podoplanin and CD31 (mean scores 3.0 for both). These pilot findings indicate that the immunophenotype of KS is anatomic site-dependent because within cutaneous KS, the HHV8-infected neoplastic spindle cells exhibit a predominantly lymphatic immunophenotype, supporting a lymphatic endothelial differentiation in this context. By contrast, mucosal KS displays a hybrid blood vascular and lymphatic phenotype. This study provides a novel methodological framework for lineage assessment in vascular neoplasms and highlights the influence of microenvironment on KS tumor phenotype.