Verrucous carcinoma of the oesophagus is a genetically distinct subtype of oesophageal squamous cell carcinoma

Abstract

Verrucous carcinoma of the oesophagus is a genetically distinct subtype of oesophageal squamous cell carcinoma Aims: 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. Methods and results: 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. Conclusions: 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.

Histomorphology and Molecular Profiling of Well-Differentiated Squamous Cell Carcinoma of the Esophagus Including its Unusual Variants

“…Isidro et al reported the first molecular study on VC. 33 Unlike conventional ESC, TP53 mutations were much less likely to be detected in VC. Copy number variants for CDKN2A, CDKN2B, and CCND1 were significantly less frequent in VC than in conventional ESC.…”

“…A non-invasive component of verrucous carcinoma adjacent to invasive verrucous carci- noma depicted in one paper demonstrated exophytic growth with verruciform architecture, preserved epithelial maturation, abrupt keratinization, and lack of nuclear overlapping or atypia. 33 Sequencing of the non-invasive squamous component showed nearly identical mutations in SMARCA4, FBXW7, and NOTCH1 (Table 1) compared to the invasive squamous component. 33 Cases 2 and 3 in this series showed the morphology of carcinoma cuniculatum in the deep portion of the lesion with keratin-filled cysts.…”

“…33 Sequencing of the non-invasive squamous component showed nearly identical mutations in SMARCA4, FBXW7, and NOTCH1 (Table 1) compared to the invasive squamous component. 33 Cases 2 and 3 in this series showed the morphology of carcinoma cuniculatum in the deep portion of the lesion with keratin-filled cysts. Both cases showed mutated SMARCA4, FBXW7, and NOTCH1 but wild-type TP53.…”

“…23 Multiple large-scale comprehensive studies have identified recurrent genetic alterations in ESC, including TP53, PIK3CA, NOTCH1, and FAT1 (Table 2). 24,[26][27][28][29][30][31][32][33] ESC also harbors frequent genomic amplifications of CCND1 and SOX2 and/or TP63. 34 The TP53 mutation has been the most common genetic alteration identified in ESC (60% to 92%), followed by NOTCH1 mutation (8% to 32%) and PIK3CA mutation (5% to 17%).…”

Laryngeal verrucous cell carcinoma

“…Verrucous carcinoma may be found in the entire mucosa of the upper aerodigestive tract, including oral cavity, pharynx, cervical esophagus, and nasal cavities [30,31 ▪ ]. In the larynx, the most common subsites of LVC are the glottis and supraglottis (Table 1) [8–10,12–17,24,32–38].…”