Aksionau Aliaksandr, Silva Roberto A, Hartman Brandon, Flowers Ashley
Department of Pathology and Translational Pathobiology, LSU Health Shreveport, Shreveport, LA, USA.
Department of Pathology, Ochsner LSU Health, Shreveport, LA, USA.
Transl Androl Urol. 2023 Aug 31;12(8):1283-1295. doi: 10.21037/tau-23-101. Epub 2023 Aug 14.
Na/H exchanger (NHE) maintains the alkaline pH of epithelial cells working at the cellular membrane and exchanging H/Na ions. In renal tubular epithelial cells, the reabsorption of NaCl is implemented by NHE3 isoform, which is regulated by NHE regulatory factor-1 (NHERF1). Normally situated at the apical zones of proximal tubular cells, NHERF1 participates in cytoskeletal reorganization and signal transduction facilitating structural stability and ion exchange. Based on an extensive search in English literature, NHERF1/EBP50 immunoexpression has been studied in breast, colon, and other tumors with only one study on 21 cases of renal cell carcinomas (RCC).
Using NHERF1/EBP50 immunohistochemistry (IHC) on 64 (82%) RCCs (34 clear cells, 21 papillary and 9 chromophobe types) and 14 (18%) oncocytomas, we evaluated and scored NHERF1/EBP50 immunoexpression depending on the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading system followed by ultrastructural identification of microlumen-like structures (MLS) in clear cell renal cell carcinomas (ccRCC).
Staining patterns varied throughout the tumors and within individual tumors. Only ccRCC showed unique MLS within the cytoplasm of tumor cells. All neoplasia-transformed tubular cells, regardless of the tumor grade and stage, had altered immunoexpression of NHERF1/EBP50 ranging from complete absence to aberrant expression in the luminal cell membrane, nuclear or cytoplasmic localizations.
Only ccRCC showed unique dot-like condensations of immunostaining/MLS at membranous, submembranous, and paranuclear localizations. The latter two localizations were mainly observed in the combined WHO/ISUP grade 1 and 2 group compared to the combined group of grade 3 and 4 tumor samples (P=0.0146 and P<0.0001, respectively). Ultrastructurally, the MLS were identified as thick microvilli trapped by a single-layer membrane, displaced into the cytoplasm and ranging from 400 nm to 3.5 µm. These significant ultrastructural reorganizations may contribute to tumor progression, metastasis, and drug resistance.
钠/氢交换体（NHE）通过在细胞膜上交换氢/钠离子来维持上皮细胞的碱性pH值。在肾小管上皮细胞中，氯化钠的重吸收由NHE3亚型实现，其受NHE调节因子-1（NHERF1）调控。NHERF1通常位于近端肾小管细胞的顶端区域，参与细胞骨架重组和信号转导，促进结构稳定性和离子交换。基于对英文文献的广泛检索，NHERF1/EBP50免疫表达已在乳腺癌、结肠癌和其他肿瘤中进行了研究，仅对21例肾细胞癌（RCC）进行了一项研究。
我们对64例（82%）RCC（34例透明细胞型、21例乳头状和9例嫌色细胞型）和14例（18%）嗜酸细胞瘤进行了NHERF1/EBP50免疫组织化学（IHC）检测，并根据世界卫生组织（WHO）/国际泌尿病理学会（ISUP）分级系统对NHERF1/EBP50免疫表达进行评估和评分，随后对透明细胞肾细胞癌（ccRCC）中的微管腔样结构（MLS）进行超微结构鉴定。
整个肿瘤及单个肿瘤内的染色模式各不相同。仅ccRCC在肿瘤细胞胞质内显示出独特的MLS。所有肿瘤转化的肾小管细胞，无论肿瘤分级和分期如何，NHERF1/EBP50的免疫表达均发生改变，从完全缺失到在管腔细胞膜上的异常表达、核定位或胞质定位。
仅ccRCC在膜性、膜下和核旁定位处显示出独特的免疫染色点状凝聚/MLS。与3级和4级肿瘤样本合并组相比，后两种定位主要在WHO/ISUP 1级和2级合并组中观察到（分别为P = 0.0146和P < 0.0001）。超微结构上，MLS被鉴定为被单层膜包裹的粗大微绒毛，移位至胞质内，长度在400 nm至3.5 µm之间。这些显著的超微结构重组可能有助于肿瘤进展、转移和耐药。
