Anaplastic Kaposi Sarcoma: A Clinicopathologic and Molecular Genetic Analysis.

Kaposi sarcoma (KS) is an HHV8-associated vascular proliferation that most often involves the skin. Rarely, KS shows marked nuclear atypia or pleomorphism; such examples are known as "anaplastic" KS. This poorly characterized variant often pursues an aggressive course; little is known of its genetic landscape. This study evaluated the clinicopathologic and genomic features of anaplastic KS. We identified 9 anaplastic KS cases from 7 patients and 8 conventional KS cases, including a matched conventional KS and primary-metastasis anaplastic KS pair from a single patient (anaplastic KS diagnosed 9 years after conventional KS). All patients with anaplastic KS were male, aged 51-82 years, who had locally aggressive tumors predominantly affecting the soft tissue and bone of the lower extremities (5/7). Four patients were known to be HIV-positive (all on antiretrovirals), 2 were HIV-negative, and one was of unknown HIV status. The tumors showed angiosarcoma-like or pleomorphic spindle cell sarcoma morphology. Plasma cell-rich chronic inflammation and hemosiderin deposition were commonly present. Single nucleotide polymorphism (SNP) based chromosomal microarray analysis showed the anaplastic KS cohort to demonstrate highly recurrent whole chromosome (chr) gains of chr 7, 11, 19, and 21, which primarily affected olfactory and G-protein coupled receptor (GPCR) signaling, and losses of chr6_q and chrY. Compared to conventional KS, anaplastic KS cases showed significantly more total copy number alterations (CNAs) and more frequent gains of chr7 and chr11_q13.1 (MARK2, RELA, and ESRRA; including high copy number gain in 1 case). Pathway analysis demonstrated these gains preferentially affected genes that facilitate cyclin-dependent cell signaling. Further, anaplastic KS cases were phylogenetically distinct from conventional KS cases, including the patient-matched primary-metastasis anaplastic KS pair and conventional KS. Our study is the first to demonstrate that a more complex genome and distinct CNAs distinguish anaplastic KS from conventional KS. Gains of chr7 and chr11_q13.1 appear central to biological transformation.