Kerr Darcy A, Busarla Satya Vara Prasad, Gimbel Devon C, Sohani Aliyah R, Nazarian Rosalynn M
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
Department of Pathology, Aga Khan Hospital, Kisumu, Kenya 40100.
Hum Pathol. 2017 Jul;65:157-165. doi: 10.1016/j.humpath.2017.05.002. Epub 2017 May 12.
Kaposi sarcoma (KS) is a locally progressive, intermediate-grade vascular neoplasm with no known cure, high recurrence rates, and potential for wide dissemination. Low efficacy and high toxicity limit current therapeutic options for advanced disease. Activation of mammalian target of rapamycin (mTOR), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and c-kit signaling pathways has been implicated in KS pathogenesis and may suggest a role for targeted inhibitors. KS cases were retrospectively retrieved (N=274), most (90%) associated with human immunodeficiency virus. Tissue microarray slides were stained with human herpes virus-8, Friend leukemia integration 1 transcription factor, CD117 (c-kit), phospho-S6 (pS6), PDGF receptor-β, VEGF, and phospho-mTOR. Both intensity and extent of staining were scored. Multiplying these scores for each core yielded total staining H-scores. Human herpes virus-8 was positive in 87% and Friend leukemia integration 1 transcription factor in 95.7% of cases. Most were also VEGF+ (97.6%), pS6+ (95.7%), CD117+ (92.5%), and PDGFRB+ (87.4%). Approximately half (55.6%) were phospho-mTOR+. There was no significant difference in staining among patients with low (<500 cells/mm) or preserved CD4 T-cell counts. Immunohistochemistry confirms upregulation of the mTOR, PDGF, VEGF, and c-kit pathways in a large cohort of KS samples. Of proteins tested, pS6, downstream of mTOR, demonstrated the highest proportion of strong positivity (67.1%). These results support the possibility of using targeted inhibitors in KS. Overexpression was independent of CD4 count, suggesting that even patients with low counts may be targeted therapy candidates.
卡波西肉瘤（KS）是一种局部进展性、中度恶性的血管肿瘤，目前尚无治愈方法，复发率高，且有广泛播散的可能。晚期疾病的当前治疗选择疗效低且毒性高。雷帕霉素靶蛋白（mTOR）、血小板衍生生长因子（PDGF）、血管内皮生长因子（VEGF）和c-kit信号通路的激活与KS发病机制有关，可能提示靶向抑制剂的作用。回顾性检索KS病例（n = 274），大多数（90%）与人类免疫缺陷病毒相关。组织微阵列玻片用人类疱疹病毒8型、Friend白血病整合1转录因子、CD117（c-kit）、磷酸化S6（pS6）、PDGF受体-β、VEGF和磷酸化mTOR进行染色。对染色强度和范围进行评分。将每个核心的这些评分相乘得出总染色H评分。87%的病例中人类疱疹病毒8型呈阳性，95.7%的病例中Friend白血病整合1转录因子呈阳性。大多数病例也为VEGF+（97.6%）、pS6+（95.7%）、CD117+（92.5%）和PDGFRB+（87.4%）。约一半（55.6%）为磷酸化mTOR+。CD4 T细胞计数低（<500个细胞/mm）或保存良好的患者之间染色无显著差异。免疫组织化学证实，在一大组KS样本中，mTOR、PDGF、VEGF和c-kit通路上调。在所检测的蛋白质中，mTOR下游的pS6显示出最高比例的强阳性（67.1%）。这些结果支持在KS中使用靶向抑制剂的可能性。过表达与CD4计数无关，这表明即使是CD4计数低的患者也可能是靶向治疗的候选者。
