類上皮型及散發性腎血管肌肉脂肪瘤的分子表達差異：

PTEN缺失和mTOR途徑活化的作用

陳昱廷、曲元正、莊正鏗

林口長庚紀念醫院 外科部泌尿科

Molecular Expression Differences between Epithelioid and Sporadic Renal Angiomyolipoma: The Role of PTEN Loss and mTOR Pathway Activation

Yu-Ting Chen, Yuan-Cheng Chu, Cheng-Keng Chuang

Division of Urology, Department of Surgery, LinKou Chang Gung Memorial Hospital, Taoyuan, Taiwan

Purpose: Renal angiomyolipoma (AML) is a rare and heterogeneous group of tumors composed of varying proportions of blood vessels, smooth muscle, and adipose tissue. Two subtypes of AML have been identified: epithelioid renal angiomyolipoma (eAML) and sporadic renal angiomyolipoma (sAML). eAML is a more aggressive subtype associated with a higher risk of malignancy, while sAML typically exhibits a benign clinical course. Despite the differences in clinical behavior, the molecular expression patterns distinguishing eAML and sAML remain poorly understood. The current study aims to investigate the molecular expression differences between these two subtypes, focusing on the role of PTEN loss and mTOR pathway activation in the pathogenesis of eAML.

Materials and Methods: Patients diagnosed with AML who require surgery were identified in clinical settings, and their background information were obtained, including gender, age, BMI, renal function, tumor size, and whether tumor hemorrhage or not. After obtaining informed consent, peripheral blood samples are collected preoperatively, as well as postoperative specimens. Three independent physicians with expertise in the field examined the immunostaining of the tumor tissues and assigned an H-score based on the intensity and extent of the staining observed and subsequently averaged to obtain a final consensus H-score for each tumor tissue sample.

Results: There were 20 patients of eAML and 28 patients of sAML included in our analysis. Our investigation revealed that eAML exhibited much lower PTEN levels than those of sAML (H-score: 157.6±27.0 vs 182.3±32.7, p=0.006). This intriguing observation suggests a PTEN loss specific to the eAML subtype. Likewise, our data supported the idea that the mTOR pathway is activated in eAML patients, with significantly higher levels of S6, pS6, and pmTOR (p=0.004, 0.045, and 0.03, respectively). Importantly, these compounds play critical roles in the mTOR pathway. As a tumor suppressor gene, PTEN plays a crucial role in preventing uncontrolled cell growth. Consequently, its loss facilitates tumorigenesis, primarily by increasing cell proliferation, survival, migration, and invasion. In light of these insights, one might conclude that the aggressive nature of eAML could be linked to PTEN loss and mTOR pathway activation.

Conclusion: In conclusion, this study has validated the loss of PTEN and the enhanced expression of the mTOR signaling pathway in eAML. These findings confirm that, in clinical settings, the use of mTOR inhibitors (such as Everolimus) can effectively reduce tumor size, thus facilitating subsequent treatments.