Diagnostic and Research Institute of Pathology.
Department of Obstetrics and Gynecology, Medical University Graz, Graz, Austria.
Am J Surg Pathol. 2022 Feb 1;46(2):147-158. doi: 10.1097/PAS.0000000000001778.
Recently, the World Health Organization (WHO) recognized human papilloma virus (HPV)-independent invasive cervical squamous cell carcinoma (SCC) without recognizing the existence of precursor lesions. This is a detailed characterization of 3 preinvasive lesions and 6 invasive SCC negative for HPV-DNA (32 genotypes), HPV-mRNA (14 genotypes) and genomic HPV sequencing. We evaluated histologic features, expression of p16ink4a, p53, CK7, and CK17, aberrations in 50 cancer genes and chromosomal copy number variations. HPV-negative preinvasive lesions were extensive basaloid or highly differentiated keratinizing intraepithelial proliferations of 3 to 20 cell layers thickness, partly with prominent cervical gland involvement. Overall, 2/3 intraepithelial lesions and the in situ component of 1/6 SCC showed p16ink4a block staining, while 1/6 in situ component revealed heterogenous p16ink4a staining. All invasive components of keratinizing SCC were p16ink4a-negative. Preinvasive and invasive SCC showed inconsistent CK7 and CK17 staining. Nuclear p53 overexpression was restricted to the TP53 gene mutated SCC. The highly vascularized peritumoral stroma showed a dense inflammatory infiltrate including plasma cells and intratumoral and peritumoral eosinophilic granulocytes. Inconsistent somatic gene mutations (PIK3CA, STK11, TP53, SMARC2B, and GNAS) occurred predominantly in nonhotspot locations at low mutational frequency in 3/6 SCC. Consistent aberrations included the pathogenic (angiogenic) germline polymorphism Q472H in the KDR gene (7/9 patients), and chromosome 3q gains (4/9 patients). In conclusion, HPV-negative intraepithelial cervical precancerous lesions exist, either as highly differentiated keratinized intraepithelial proliferations reminiscent of differentiated vulvar intraepithelial neoplasia, or undifferentiated basaloid intraepithelial lesions with occasional p16ink4a block staining resembling high-grade squamous intraepithelial lesion. Gains of chromosome 3q, angiogenic germline variants the inflammatory infiltrate may contribute to progression of HPV-negative cervical carcinogenesis.
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），而没有认识到其前驱病变的存在。这是对 3 种 HPV-DNA（32 种基因型）、HPV-mRNA（14 种基因型）和 HPV 基因组测序均为阴性的浸润前病变和 6 例 SCC 的详细特征描述。我们评估了组织学特征、p16ink4a、p53、CK7 和 CK17 的表达、50 个癌症基因的畸变以及染色体拷贝数变异。HPV 阴性的浸润前病变是广泛的基底样或高度分化的角化性上皮内增生，厚度为 3 至 20 个细胞层，部分伴有明显的宫颈腺体受累。总体而言，3 种上皮内病变中的 2/3 和 6 例 SCC 中的 1/6 原位病变显示 p16ink4a 阻断染色，而 6 例 SCC 中的 1/6 原位病变显示异质性 p16ink4a 染色。所有角化 SCC 的浸润性成分均为 p16ink4a 阴性。浸润前和浸润性 SCC 的 CK7 和 CK17 染色不一致。核 p53 过表达仅限于 TP53 基因突变的 SCC。富含血管的肿瘤周围基质表现为密集的炎症浸润，包括浆细胞和肿瘤内及肿瘤周围嗜酸性粒细胞。不一致的体细胞基因突变（PIK3CA、STK11、TP53、SMARC2B 和 GNAS）主要发生在非热点位置，突变频率低，在 6 例 SCC 中的 3 例中发生。一致的畸变包括致病性（血管生成）种系多态性 Q472H 在 KDR 基因（9 例患者中的 7 例）中，以及染色体 3q 增益（9 例患者中的 4 例）。总之，HPV 阴性的宫颈上皮内癌前病变存在，要么是高度分化的角化上皮内增生，类似于分化型外阴上皮内瘤变，要么是未分化的基底样上皮内病变，偶尔伴有 p16ink4a 阻断染色，类似于高级别鳞状上皮内病变。3q 染色体增益、血管生成种系变体和炎症浸润可能有助于 HPV 阴性宫颈癌变的进展。
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