Wang X J, Liu E J, Yang M L, Li S L, Wei J G
Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Zhonghua Bing Li Xue Za Zhi. 2025 Sep 8;54(9):947-952. doi: 10.3760/cma.j.cn112151-20241230-00888.
To explore the clinicopathological and molecular genetic characteristics of anaplastic lymphoma kinase (ALK)-rearranged renal cell carcinoma (RCC), including a rare case with the TPM1-ALK gene subtype. Three cases of ALK-rearranged RCC diagnosed in the Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China from January 2020 to December 2024 were collected. Their clinical pathological and next-generation sequencing (NGS) data were analyzed. Relevant literature was also reviewed, and follow-ups were carried out. Among the three patients, there were 1 female (case 1) and 2 males (cases 2 and 3), with the ages of 29,41 and 44 years, respectively. All of them were presented with space-occupying renal lesions. Case 1 (KIAA1217-ALK RCC) showed mixed cystic and solid components under the microscope, with tubular, papillary, and cribriform arrangements. The tumor cells had clear boundaries, and were cubic or low columnar, arranged in a single layer, pseudostratified or in sheets. The cytoplasm was abundant and eosinophilic, and part of the cytoplasm was vacuolated, as if there was accumulation of mucoid substances. The tumor cell nuclei were oval with prominent nucleoli. A large amount of mucus and inflammatory cell infiltration were noted in the stroma. Case 2 (TPM1-ALK RCC) showed a papillary growth pattern, with small, slender papillae accompanied by branches. The cells were arranged in a single layer, and the cytoplasm was either eosinophilic or clear. Foamy cells were aggregated in the stroma, accompanied by psammoma body-like calcifications. Case 3 (EML4-ALK RCC) was characterized by papillary and tubulocystic structures. The cytoplasm was abundant and eosinophilic. The tumor cell nuclei were large, with prominent nucleoli. There was conspicuous infiltration of lymphocytes and neutrophils in the fibromuscular stroma. The tumor cells all expressed epithelial markers, PAX8, GATA3, P504s and FH. ALK (5A4) staining showed diffuse strong expression in the cytoplasm, while TFE-3 was positive (nuclear stain) only in case 1 and case 3. The fluorescence in situ hybridization showed that ALK gene rearrangement was present in all three cases, while TFE-3 gene rearrangement/mutation was not detectable in case 1 and case 3. NGS showed the KIAA1217::ALK fusion (the fusion site in the exon 11 of KIAA1217 and exon 18 of ALK) in case 1, the TPM1::ALK fusion (the exon 8 of TPM1 and exon 20 of ALK) in case 2, and the EML4::ALK fusion (the exon 2 region of EML4 and the exon 20 region of ALK) in case 3. ALK-rearranged RCC has unique molecular characteristics. Its histological morphology is easily confused with that of papillary RCC and TFE3-rearranged RCC. Both immunohistochemistry and gene rearrangement tests should be used to confirm the diagnosis.
探讨间变性淋巴瘤激酶（ALK）重排肾细胞癌（RCC）的临床病理及分子遗传学特征，包括1例罕见的伴TPM1-ALK基因亚型的病例。收集了2020年1月至2024年12月在中国郑州郑州大学第一附属医院病理科诊断的3例ALK重排RCC病例。分析其临床病理及二代测序（NGS）数据。还回顾了相关文献并进行了随访。3例患者中，女性1例（病例1），男性2例（病例2和病例3），年龄分别为29岁、41岁和44岁。均表现为肾脏占位性病变。病例1（KIAA1217-ALK RCC）镜下可见囊实性混合成分，呈管状、乳头状和筛状排列。肿瘤细胞边界清晰，呈立方或低柱状，单层排列、假复层排列或成片排列。细胞质丰富且呈嗜酸性，部分细胞质呈空泡状，仿佛有黏液样物质积聚。肿瘤细胞核呈椭圆形，核仁明显。间质中可见大量黏液及炎性细胞浸润。病例2（TPM1-ALK RCC）呈乳头状生长模式，有小而细长的乳头并伴有分支。细胞单层排列，细胞质呈嗜酸性或透明。泡沫细胞聚集于间质中，伴有砂粒体样钙化。病例3（EML4-ALK RCC）以乳头状和微囊状结构为特征。细胞质丰富且呈嗜酸性。肿瘤细胞核大，核仁明显。纤维肌性间质中有明显的淋巴细胞和中性粒细胞浸润。肿瘤细胞均表达上皮标志物PAX8、GATA3、P504s和FH。ALK（5A4）染色显示细胞质弥漫性强表达，而TFE-3仅在病例1和病例3中呈阳性（核染色）。荧光原位杂交显示3例均存在ALK基因重排，而病例1和病例3未检测到TFE-3基因重排/突变。NGS显示病例1存在KIAA1217::ALK融合（融合位点在KIAA1217的外显子11和ALK的外显子18），病例2存在TPM1::ALK融合（TPM1的外显子8和ALK的外显子20），病例3存在EML4::ALK融合（EML4的外显子2区域和ALK的外显子20区域）。ALK重排RCC具有独特的分子特征。其组织形态学易与乳头状RCC和TFE3重排RCC混淆。诊断需结合免疫组化及基因重排检测。
