Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Histopathology. 2021 Oct;79(4):642-649. doi: 10.1111/his.14395. Epub 2021 Jul 8.
Oesophageal verrucous carcinoma (VSCC) is a rare and morphologically distinct type of oesophageal squamous cell carcinoma (SCC). Diagnosing VSCC on biopsy material is challenging, given the lack of significant atypia and the presence of keratinising epithelium and exophytic growth. The molecular pathogenesis of VSCC remains unclear. The aim of this study was to characterise the genomic landscape of VSCC in comparison to conventional oesophageal SCC.
Three cases of VSCC from the Brigham and Women's Hospital pathology archive were identified. Formalin-fixed, paraffin-embedded (FFPE) tumour tissue was used for p16 immunohistochemistry (IHC), high-risk human papillomavirus (HPV) in-situ mRNA hybridisation (ISH) and DNA isolation. Tumour DNA was sequenced using a targeted massively parallel sequencing assay enriched for cancer-associated genes. Three additional cases of VSCC were identified by image review of The Cancer Genome Atlas (TCGA) oesophageal SCC cohort. VSCC cases were negative for p16 IHC and high-risk HPV ISH. TP53 mutations (P < 0.001) and copy number variants (CNVs) for CDKN2A (P < 0.001), CDKN2B (P < 0.01) and CCND1 (P < 0.01) were absent in VSCC and significantly less frequent in comparison to conventional SCC. Five VSCC cases featured SMARCA4 missense mutations or in-frame deletions compared to only four of 88 conventional SCC cases (P < 0.001). VSCC featured driver mutations in PIK3CA, HRAS and GNAS. Recurrent CNVs were rare in VSCC.
VSCC is not only morphologically but also genetically distinct from conventional oesophageal SCC, featuring frequent SMARCA4 mutations and infrequent TP53 mutations or CDKN2A/B CNVs. Molecular findings may aid in establishing the challenging diagnosis of VSCC.
食管疣状癌（VSCC）是一种罕见的、形态独特的食管鳞状细胞癌（SCC）。由于缺乏明显的异型性和角化上皮以及外生性生长的存在，在活检材料上诊断 VSCC 具有挑战性。VSCC 的分子发病机制尚不清楚。本研究旨在比较常规食管 SCC ，对 VSCC 的基因组图谱进行特征描述。
从布莱根妇女医院病理档案中确定了 3 例 VSCC 病例。使用福尔马林固定、石蜡包埋（FFPE）肿瘤组织进行 p16 免疫组化（IHC）、高危型人乳头瘤病毒（HPV）原位 mRNA 杂交（ISH）和 DNA 分离。使用针对癌症相关基因富集的靶向大规模平行测序检测肿瘤 DNA 测序。通过对癌症基因组图谱（TCGA）食管 SCC 队列的图像回顾，确定了另外 3 例 VSCC 病例。VSCC 病例 p16 IHC 和高危 HPV ISH 均为阴性。TP53 突变（P<0.001）和 CDKN2A（P<0.001）、CDKN2B（P<0.01）和 CCND1（P<0.01）的拷贝数变异（CNVs）在 VSCC 中缺失，与常规 SCC 相比明显减少。与 88 例常规 SCC 病例中的 4 例相比，5 例 VSCC 病例存在 SMARCA4 错义突变或框内缺失（P<0.001）。VSCC 具有 PIK3CA、HRAS 和 GNAS 的驱动突变。VSCC 中重现性 CNV 罕见。
VSCC 不仅在形态上，而且在遗传上也与常规食管 SCC 不同，其特征是频繁的 SMARCA4 突变和不频繁的 TP53 突变或 CDKN2A/B CNVs。分子发现可能有助于建立具有挑战性的 VSCC 诊断。
