Diagnostic and Research Institute of Pathology, Medical University Graz, Graz, Austria.
Am J Surg Pathol. 2023 Dec 1;47(12):1449-1460. doi: 10.1097/PAS.0000000000002130. Epub 2023 Sep 28.
Compared with vulva, precursor lesions of human papillomavirus (HPV)-independent invasive squamous cell carcinoma (SCC) of the penis are insufficiently characterized. We analyzed the histologic and immunohistochemical characteristics of 70 peritumoral precursor lesions and correlated them with the histology and mutational profile of the adjacent HPV-negative invasive penile SCC. Atypical basal keratinocyte proliferation with variously elongated epithelial rete with premature squamatiziation, but regular superficial cornification, termed differentiated penile intraepithelial neoplasia (d-PeIN), were identified adjacent to 42/70 (60%) SCC (36/42 keratinizing ( P <0.001); 3 papillary, and 1 each verrucous, clear cell, sarcomatoid SCC). d-PeIN were associated with chronic inflammatory dermatoses (32/42; P <0.001), p53 overexpression (26/42; P <0.001), and hotspot mutations in TP53 (32/42; P <0.001), CDKN2A (26/42; P <0.001) or both (21/42; P =0.003) in the adjacent SCC. Cytoplasmic p16 ink4a overexpression in 5/42 d-PeIN correlated with CDKN2A missense mutations in the adjacent SCC. In all, 21/70 (30%) cornified verrucous or glycogenated verruciform precursors with minimal atypia and wild-type p53 (18/21; P <0.001) occurred adjacent to verrucous or papillary SCC (17/21; P <0.001) and keratinizing (4/21) SCC, which harbored mutations in HRAS and/or PIK3CA (12/21; P <0.004). Undifferentiated p16 ink4a -negative full-thickness precursors were identified in 7/70 (10%) SCC. Four histologically different HPV-independent penile precursor lesions can be assigned to 2 major genetic/biological pathways with characteristic highly differentiated precursors requiring different clinical management decisions. These include d-PeIN in chronic inflammatory dermatoses, with p53 overexpression and TP53/CDKN2A mutations, and the p53 wild-type verrucous and verruciform precursors unassociated with dermatoses, but with mutations in oncogenes PIK3CA and HRAS .
与外阴相比，人类乳头瘤病毒（HPV）独立的阴茎浸润性鳞状细胞癌（SCC）的前驱病变特征不足。我们分析了 70 例肿瘤周围前驱病变的组织学和免疫组织化学特征，并将其与相邻 HPV 阴性浸润性阴茎 SCC 的组织学和突变谱相关联。与 42/70（60%）SCC（36/42 角化型（P <0.001）；3 例乳头状，1 例疣状，1 例透明细胞，1 例肉瘤样 SCC）相邻的是具有不同程度伸长的上皮网和过早角化的异型基底角质形成细胞增生，但有规则的浅表角化，称为分化型阴茎上皮内瘤变（d-PeIN）。d-PeIN 与慢性炎症性皮肤病（32/42；P <0.001）、p53 过表达（26/42；P <0.001）和 TP53（32/42；P <0.001）、CDKN2A（26/42；P <0.001）或两者（21/42；P =0.003）的热点突变相关，相邻 SCC。5/42 d-PeIN 中细胞质 p16 ink4a 过表达与相邻 SCC 中 CDKN2A 错义突变相关。总之，70 例中有 21 例（30%）角化性疣状或糖原性疣状前驱病变，伴有最小异型性和野生型 p53（18/21；P <0.001），与疣状或乳头状 SCC（17/21；P <0.001）和角化 SCC（4/21）相邻，这些 SCC 携带 HRAS 和/或 PIK3CA 突变（12/21；P <0.004）。在 70 例 SCC 中发现了 7 例（10%）未分化的 p16 ink4a 阴性全层前驱病变。有 4 种不同组织学的 HPV 非依赖性阴茎前驱病变可分为 2 种主要的遗传/生物学途径，具有特征性的高度分化前驱病变，需要不同的临床管理决策。这些包括慢性炎症性皮肤病中的 d-PeIN，p53 过表达和 TP53/CDKN2A 突变，以及与皮肤病无关的 p53 野生型疣状和疣状前驱病变，但有致癌基因 PIK3CA 和 HRAS 的突变。
