Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Appl Immunohistochem Mol Morphol. 2020 Aug;28(7):495-500. doi: 10.1097/PAI.0000000000000781.
NUT midline carcinoma (NMC) is a rare, aggressive poorly differentiated carcinoma genetically defined by NUTM1 gene rearrangement. The purpose of this study was to determine the tumor mutational burden (TMB) and the expression of immunohistochemical (IHC) markers in NMCs that are generally used to identify patients that might benefit from checkpoint immunotherapy. Three cases in a 39-year-old male (case 1) and two 13-year-old females (cases 2, 3) were identified from departmental files, with confirmation by NUT IHC and 15q14 rearrangement by fluorescent in situ hybridization. Normal-tumor paired whole exome sequencing (WES) was applied to determine TMB. IHC for DNA mismatch repair proteins, Programmed cell death ligand 1, programmed cell death 1 (PD1), and CD8 was also performed. WES yielded a TMB of 7.61 and 1.52 per Mbp in the primary and pulmonary metastasis in case 1, respectively, and a TMB of 1.04 per Mbp in the primary tumor of case 2. Programmed cell death ligand 1 tumor proportion score was 20%, 1%, and 0% and combined positive score was 25, 5, and 0 in cases 1, 2, and 3, respectively; PD1 stain counts were 25, 52, and 35 per high-power field and the PD1/CD8 ratio was 95%, 95%, and 99% in cases 1, 2, and 3, respectively. The CD8 count per high-power field was 15, 33, and 30 per high-power field in cases 1, 2, and 3, respectively. Mismatch repair IHCs showed retained staining. Although the number of cases is limited, this study is the first to investigate checkpoint immunotherapy markers in NMCs and the results demonstrate no clear biomarker association. However, the results suggest that, if checkpoint therapy is under consideration, a comprehensive workup utilizing WES and IHC is warranted.
NUT 中线癌（NMC）是一种罕见的、侵袭性的低分化癌，在基因上由 NUTM1 基因重排定义。本研究的目的是确定 NMC 的肿瘤突变负担（TMB）和免疫组织化学（IHC）标志物的表达，这些标志物通常用于识别可能受益于检查点免疫治疗的患者。从科室档案中确定了 3 例 39 岁男性（病例 1）和 2 例 13 岁女性（病例 2、3），通过 NUT IHC 和荧光原位杂交证实 15q14 重排。应用全外显子测序（WES）确定 TMB。还进行了 DNA 错配修复蛋白、程序性细胞死亡配体 1（PD-L1）、程序性细胞死亡 1（PD-1）和 CD8 的免疫组化检测。在病例 1 的原发性肿瘤和肺转移中，WES 分别产生了 7.61 和 1.52 个突变/Mbp 的 TMB，而在病例 2 的原发性肿瘤中，TMB 为 1.04 个突变/Mbp。病例 1、2 和 3 的 PD-L1 肿瘤比例评分分别为 20%、1%和 0%，综合阳性评分分别为 25%、5%和 0%；病例 1、2 和 3 的 PD-1 染色计数分别为每高倍镜 25、52 和 35 个，PD-1/CD8 比值分别为 95%、95%和 99%；病例 1、2 和 3 的每高倍镜 CD8 计数分别为 15、33 和 30。错配修复 IHC 显示保留染色。尽管病例数量有限，但本研究首次对 NMC 中的检查点免疫治疗标志物进行了研究，结果表明没有明确的生物标志物相关性。然而，结果表明，如果考虑进行检查点治疗，需要利用 WES 和 IHC 进行全面检查。
