Diagnostic and Research Institute of Pathology.
Department of Obstetrics and Gynecology, Medical University Graz, Graz, Austria.
Am J Surg Pathol. 2023 Aug 1;47(8):942-949. doi: 10.1097/PAS.0000000000002067. Epub 2023 Jun 7.
Recently, the World Health Organization (WHO) recognized the existence of human papillomavirus (HPV)-independent invasive cervical squamous cell carcinoma (SCC), but HPV-independent precursor lesions were not included due to the lack of description of this rare entity. We present the histologic spectrum of highly differentiated squamous HPV-negative and p16 ink4a -negative precursor lesions adjacent to and/or preceding invasive HPV-negative cervical SCC in 3 patients. The histologic features resembled those described for vulvar HPV-negative precursor lesions. One precursor featured a proliferation of atypical basal keratinocytes with mitotic activity, premature squamatization in elongated epithelial rete, and mostly regular superficial squamous differentiation with TP53 mutation and immunohistochemical p53 overexpression termed differentiated cervical intraepithelial neoplasia (d-CIN). The other 2 precursors included verruciform acanthosis with plump rete, minimal atypia, and an EGFR mutation that resembled vulvar acanthosis with altered differentiation, and an exophytic papillary proliferation with a PIK3CA mutation resembling the differentiated exophytic vulvar intraepithelial lesion. Two precursors that preceded the invasive SCC harbored an additional pathogenic SMARCB1 mutation. The cytologic smears of d-CIN revealed 3-dimensional branched basaloid tubular structures and eosinophilic squamous cell clusters mimicking the histologic features. In conclusion, highly differentiated cervical HPV-negative precursors are characteristic intraepithelial squamous lesions with somatic mutations that resemble those described in vulvar HPV-independent carcinogenesis. For optimal reproducibility, we propose a simplistic classification of these HPV-negative cervical precursors in TP53 -mutated d-CIN and p53 wild-type verruciform intraepithelial neoplasia.
最近，世界卫生组织（WHO）承认了人乳头瘤病毒（HPV）独立的浸润性宫颈鳞状细胞癌（SCC）的存在，但由于缺乏对这种罕见实体的描述，HPV 独立的前体病变并未包括在内。我们在 3 例患者中展示了与 HPV 阴性浸润性宫颈 SCC 相邻和/或之前的高分化 HPV 阴性和 p16ink4a 阴性鳞状前驱病变的组织学谱。组织学特征类似于描述的外阴 HPV 阴性前驱病变。一个前体表现为具有有丝分裂活性的非典型基底角质形成细胞的增殖，伸长的上皮网中早熟的角化，以及大多数具有 TP53 突变和免疫组织化学 p53 过表达的规则浅表鳞状分化，称为分化型宫颈上皮内瘤变（d-CIN）。另外 2 个前体包括疣状棘皮症伴饱满的网，最小的非典型性和类似于外阴棘皮症改变分化的 EGFR 突变，以及类似于分化型外阴上皮内病变的外生性乳头状增生伴 PIK3CA 突变。在侵袭性 SCC 之前的 2 个前体中还存在额外的致病性 SMARCB1 突变。d-CIN 的细胞学涂片显示 3 维分支基底样管状结构和嗜酸性鳞状细胞簇，类似于组织学特征。总之，高分化的 HPV 阴性宫颈前体是具有体细胞突变的特征性上皮内鳞状病变，类似于外阴 HPV 独立致癌作用中描述的那些。为了获得最佳的可重复性，我们建议对这些 HPV 阴性宫颈前体进行简单的分类，即 TP53 突变的 d-CIN 和 p53 野生型疣状上皮内瘤变。
