Foundation Medicine, Inc., 150 Second Street, Cambridge, MA, 02141, USA.
Department of Pathology, State University of New York Upstate Medical University, 766 Irving Avenue, Syracuse, NY, 13210, USA.
Mod Pathol. 2020 Dec;33(12):2614-2625. doi: 10.1038/s41379-020-0584-2. Epub 2020 May 27.
Rare reports of anal carcinoma (AC) describe histologic resemblance to cutaneous cylindroma, but mutations in the tumor suppressor CYLD, the gene responsible for familial and sporadic cylindromas, have not been systematically investigated in AC. Here, we investigate CYLD-mutant AC, focusing on molecular correlates of distinct histopathology. Comprehensive genomic profiling (hybrid-capture-based DNA sequencing) was performed on 574 ACs, of which 75 unique cases (13%) harbored a CYLD mutation. Clinical data, pathology reports, and histopathology were reviewed for each CYLD-mutant case. The spectrum of CYLD mutations included truncating (n = 50; 67%), homozygous deletion (n = 10; 13%), missense (n = 16; 21%), and splice-site (n = 3; 4%) events. Compared with CYLD-wildtype AC (n = 499), CYLD-mutant ACs were significantly enriched for females (88% vs. 67%, p = 0.0001), slightly younger (median age 59 vs. 61 years, p = 0.047), and included near-universal detection of high-risk HPV sequences (97% vs. 88%, p = 0.014), predominantly HPV16 (96%). The CYLD-mutant cohort also showed significantly lower tumor mutational burden (TMB; median 2.6 vs. 5.2 mut/Mb, p < 0.00001) and less frequent alterations in PIK3CA (13% vs. 31%, p = 0.0015). On histopathologic examination, 73% of CYLD-mutant AC (55/75 cases) showed a striking cylindroma-like histomorphology, composed of aggregates of basaloid cells surrounded by thickened basement membranes and containing characteristic hyaline globules, while only 8% of CYLD-wildtype tumors (n = 34/409) contained cylindroma-like hyaline globules (p < 0.0001). CYLD-mutant carcinomas with cylindroma-like histomorphology (n = 55) showed significantly lower TMB compared with CYLD-mutant cases showing basaloid histology without the distinctive hyaline globules (n = 14) (median 1.7 vs. 4.4 mut/Mb, p = 0.0058). Only five CYLD-mutant cases (7%) showed nonbasaloid conventional squamous cell carcinoma histology (median TMB = 5.2 mut/Mb), and a single CYLD-mutant case showed transitional cell carcinoma-like histology. Within our cohort of ACs, CYLD mutations characterize a surprisingly large subset (13%), with distinct clinical and genomic features and, predominantly, a striking cylindroma-like histopathology, representing a genotype-phenotype correlation which may assist in classification of AC.
罕见的肛门癌（AC）报告描述了与皮肤圆柱瘤相似的组织学特征，但导致家族性和散发性圆柱瘤的肿瘤抑制因子 CYLD 突变并未在 AC 中得到系统研究。在这里，我们研究了 CYLD 突变型 AC，重点关注不同组织病理学的分子相关性。对 574 例 AC 进行了全面的基因组分析（基于杂交捕获的 DNA 测序），其中 75 例独特的病例（13%）存在 CYLD 突变。对每个 CYLD 突变病例进行了临床数据、病理报告和组织病理学审查。CYLD 突变的范围包括截断（n=50；67%）、纯合缺失（n=10；13%）、错义（n=16；21%）和剪接位点（n=3；4%）事件。与 CYLD 野生型 AC（n=499）相比，CYLD 突变型 AC 女性明显更为丰富（88% vs. 67%，p=0.0001），年龄略小（中位年龄 59 岁 vs. 61 岁，p=0.047），并且几乎普遍检测到高危 HPV 序列（97% vs. 88%，p=0.014），主要是 HPV16（96%）。CYLD 突变组的肿瘤突变负担（TMB）也明显较低（中位数 2.6 与 5.2 mut/Mb，p<0.00001），PIK3CA 改变的频率也较低（13%与 31%，p=0.0015）。在组织病理学检查中，73%的 CYLD 突变型 AC（55/75 例）表现出明显的圆柱瘤样形态，由基底样细胞聚集组成，周围有增厚的基底膜，并含有特征性的透明小体，而只有 8%的 CYLD 野生型肿瘤（n=34/409）含有圆柱瘤样透明小体（p<0.0001）。具有圆柱瘤样形态的 CYLD 突变型癌（n=55）与不具有特征性透明小体的 CYLD 突变型基底样组织学病例（n=14）相比，TMB 明显较低（中位数 1.7 与 4.4 mut/Mb，p=0.0058）。只有 5 例（7%）CYLD 突变型病例（n=5）表现为非基底样常规鳞状细胞癌组织学（中位 TMB=5.2 mut/Mb），1 例 CYLD 突变型病例表现为移行细胞癌样组织学。在我们的 AC 队列中，CYLD 突变特征是一个非常大的亚组（13%），具有独特的临床和基因组特征，主要是明显的圆柱瘤样组织病理学，代表着一种可能有助于 AC 分类的基因型-表型相关性。
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